SENSible Question: Wouldn’t Cellular Reprogramming Be Enough?

SENSible Question: Cellular reprogramming turns an old person’s cells young again. So can’t we fix aging by just reprogramming a person’s old cells with reprogramming factors?

This is a tantalizing idea that’s on a lot of our supporters’ minds these days. On the one hand, it’s certainly true that we lose cells with aging and that other cells become dysfunctional. And on the other hand, the cellular reprogramming experiments have in some senses rejuvenated cells in a way that can and should spark excitement — first and foremost, because the technology will greatly enable cell therapy of various kinds, which will be critical to the medical defeat of aging. But the quite rational enthusiasm for a specific technology can sometimes spark a kind of irrational biomedical exuberance so great that even some very prominent geroscientists seem to have begun to fall into a kind of fallacy of composition: the body is made up of cells; therefore, if we rejuvenate all our cells, we will rejuvenate our entire bodies.

People making this intuitive leap are in for an inelegant crash, like a runner in an obstacle course who are so focused on the goal that they both misjudge the height of a hurdle, and don’t see the mudpit that lies directly behind it. By focusing too narrowly on cells and their epigenetic status, they neglect or take too superficial an account of many kinds of cellular and molecular aging damage. We simply are not composed entirely of cells, and replacing lost cells and restoring the original differentiation of cells with epigenetic changes won’t do anything to remove or repair aging damage to the many other functional units that are lost or damaged as we age and that contribute to diseases and disabilities of aging.

Deranged by the Matrix

For one thing, there’s aging damage to the extracellular matrix. The ECM is the lattice of proteins that provide both physical structure and signaling cues for our cells and tissues, and that also have important roles of their own in the body’s movement and plumbing. At the most grossly mechanical level, your quality of life — and your life itself — will be badly impacted if the structured lattice of collagen and other proteins that give form and elasticity to your bones decays or is weakened enough to break under an impact from which a young person would bounce back with no more than a bruise. Similarly, delivering pristine cells to your brain will quickly become a wasted effort if they are subjected to the nonstop pounding of the pulse because your major arteries are still stiff (let alone a if they get hit by a more acute event like a stroke or acute kidney injury, either of which could result from an overly-stiff arterial ECM).

Cells also can’t do their job properly when they are physically impeded from doing so by age changes in the ECM. For instance, aging muscle tissue stiffens, with the result that the muscle is less able to generate eccentric force — even as the resistance also makes more force necessary in order to move one’s joints in the first place. But the stiffening isn’t happening in the muscle fibers themselves: instead, the action of the muscle is impaired in aging by the buildup of abnormally high amounts of ECM around the fibrils. The same thing happens in the aging heart, which impairs the ability of the heart to fully contract and then to relax afterward and refill with blood, contributing to heart failure.

But beyond the ways that damage to aging ECM can physically get in the way of cells doing their jobs, the cells themselves behave abnormally when they are embedded in abnormal ECM. For instance, damage to aging skin proteins impairs their ability to adhere to and provide appropriate mechanical feedback to deep skin cells (fibroblasts), causing fibroblasts to “collapse” and fail to produce new collagen. Age-related loss of a specialized ECM protein called fibronectin causes muscle stem cells to go AWOL, abandoning their “barracks” in the muscle tissue. With fewer muscle stem cells at the ready, injuries to the aging muscle are not fully repaired; conversely, restoring fibronectin levels in aged mouse muscle substantially rejuvenates the aged muscle’s repair capacity. Similarly, the age-related stiffening of the ECM in which muscle stem cells are embedded impairs their ability to reproduce and mature.

Restoration of fibronectin to the aged ECM increases the number of proliferating early muscle progenitors and muscle stem cells, and partially rejuvenates muscle repair after injury. Credit: Nature Med 22(8): 897–905.

Attack of the Amyloids

Conversely, abnormal ECM can enable bad behavior by cancer cells and other abnormal cell types, and cancer cells send out signals that effectively “till the soil” of ECM in distant organs as it begins casting out mobilized cancer cells as “seeds” for the metastasis process that actually kills most cancer patients.

In addition to damage to the ECM, another critical kind of aging damage that would impair the youthful function even of pristine reprogrammed cells is the various extracellular aggregates (“amyloids”) that accumulate outside cells. These are damaged proteins that either physically impede cells’ ability to carry out their function, or cause cellular dysfunction in other ways.

A cardinal example of the former type is cardiac amyloids such as wild-type TTR aggregates, which physically disrupt the architecture of the heart, interfering with its ability to beat. Cardiac amyloidosis is a major driver of some kinds of heart failure in older people, and appears to be almost universal in our longest-lived people at death. A good example of the latter type of amyloid-related cellular dysfunction is when beta-amyloid in its soluble (non-plaque) forms causes the branches through which brain nerve cells communicate with each other to wither away, and also aggravates microglia, turning cells that are meant to protect our neurons into blind agents of destruction. If amyloids are not cleared out, both cells sent in as replacements cells and cells that have undergone partial reprogramming in tissues will still be impaired in their ability to bring us back to health because they will still be subjected to these same assaults.

A Car Needs an Engine to Drive it to the Mechanic

So far, we’ve been thinking about using reprogramming technology either to create replacement cells for those that have been lost to aging processes, or to reprogram cells already in the tissues in order to (as advocates would have it) rejuvenate their function. These applications could in principle deal with cells that are either missing entirely, or that are still present but behaving badly due to reversible changes in their epigenetics — but they can’t do anything about cells that survive, but have suffered certain other kinds of aging damage.

For instance, cells overtaken by mitochondria with large deletion mutations (which are the most problematic kind of mitochondrial damage in aging) almost certainly can’t be restored to normal functioning through reprogramming, for a couple of reasons. First, as we discussed in a previous SENSible Question on mitochondrial mutations, reprogramming technologies require the cell’s DNA to be replicated during the cell cycle, which is why nearly all reprogramming protocols use deep skin cells or immune cells. But with only a couple of unusual exceptions, mitochondria bearing deletion mutations take over in exactly those cell types that can’t dilute them away because they don’t divide, such as brain neurons, heart muscle cells, and muscle fiber segments.

And certainly, reprogramming a cell can’t repair these large deletions, for the simple reason that there is no intact template for the missing mitochondrial genes left in the so-called “homoplasmic” cells that bear them. No one has even reported reprogramming “rho0” cells, which are the closest thing to cells harboring large deletions that can be readily maintained in cell culture.

And contrary to myth, cellular reprogramming doesn’t even repair less severe mitochondrial DNA mutations when they’re present in significant numbers in the cell. Instead, reprogramming leads to cells with different mixtures of the original cell’s intact and mutated mitochondrial genomes, with each reprogrammed cell winding up with different burdens of mutations, in part due to different fractions of healthy and mutated mitochondria persisting after the process is complete. In fact, far from fixing all the mitochondrial mutations present prior to the reprogramming process, a significant number of cells acquire mitochondrial mutations during cellular reprogramming, causing immune rejection when transplanted back into the same person they originally came from!

Damaged Beyond (Epigenetic) Repair

In all probability, the presence of mitochondrial mutations and other aging damage (such as intracellular aggregates, the abnormal splice protein lamin A, and some mutations and epimutations) is one of the main reasons why only a tiny fraction of cells exposed to reprogramming factors ever actually get reprogrammed: about 0.01–0.02% when using the original reprogramming factors, less than 1% with most recent methods, and uniformly less than 5% even in “high-efficiency” methods — and the high-efficiency methods aren’t widely used because they have other problems.

And in addition to not repairing all aging damage, reprogramming itself causes other kinds of damage to some cells that make them useless for rejuvenation biotechnology, such as the newly-created mitochondrial DNA mutations we mentioned above, or abnormal numbers of chromosomes, or the paradoxical mixed bag of reprogramming-induced senescence (RIS).

It’s unsurprising therefore that in many reports, reprogramming efficiency goes down the older the donor gets. Famously, even centenarians’ deep skin cells can be reprogrammed — but getting their cells to do so required additional reprogramming factors that are not needed to reprogram cells from younger donors, and even then, the centenarian’s cells were only reprogrammed as efficiently as those of a 74-year-old. (The finding that there isn’t much difference in the reprogramming efficiency between cells from a 74-year-old and a centenarian doesn’t contradict the general finding of age-related decline, since most people who become centenarians today (and thus without the benefit of rejuvenation biotechnologies) are gifted with a “slow-aging” genes that (by definition) retard the rate of accumulation of aging damage).

This creates a bit of an illusion: because cells bearing the most damage of certain kinds can’t be reprogrammed, many people get an exaggerated sense that the reprogramming process itself has repaired all the aging damage in a cell, when exactly those cells bearing the lowest amount of aging damage to begin with that are most likely to survive and be successfully reprogrammed in the first place.

This is evident when reprogramming cells from (or in) aged donors, including the currently-hot area of “in vivo” partial reprogramming — that is, inducing reprogramming factors directly in the cells in living organisms instead of taking cells from a donor and reprogramming them in a dish. For example, the abstract of a recent report said that such in vivo reprogramming “lead to rejuvenating effects in different tissues, such as the kidney and skin” (my emphasis), which is true as far as it goes — but actually, it only caused meaningful rejuvenating effects in these two tissues, and there are methodological problems about some of the claimed effects.

Around the same time, another study used a drug to activate reprogramming factors in all the cells in middle-aged mice’s bodies — but little actual reprogramming occurred outside of the pancreas, although their activation did lead to other favorable-looking changes in the intestine, stomach, liver, and spleen that did not apparently dependent on actually reprogramming the cells. Contrast that with what the same scientists found in an earlier study, when they activated the same transgenes but in juvenile mice instead of middle-aged adults: at that young age, there was extensive and very complete reprogramming in the pancreas, but also the stomach, intestine, and kidney — so much so that they developed tumors after reprogramming.

And while the scientists who conducted the kidney-and-spleen study had previously reported that reprogramming improved post-injury muscle repair in young animals by enhancing the function of muscle precursor cells, in their more recent report the same group found that it had no such effect in old animals.

Similarly, in another in vivo reprogramming study, which got a lot of advance press via podcast appearances, cellular reprogramming in very young mice allowed for substantial recovery of visual nerve function after their optic nerves were crushed or after artificially-induced glaucoma. However, nearly all of the individual experiments in the report were actually carried out in either extremely young or at worst early middle-aged mice, who by that very fact have relatively low levels of pre-existing aging damage in their cells. And despite the way it was sometimes described in the media (and to an extent even in the published scientific paper), it’s evident that the older (and thus more damaged) the animals were when their visual nerves were injured, the less effective reprogramming was at protecting or restoring their function.

Reprogramming factors (OSK) were progressively less effective at protecting and restoring visual nerve integrity and function as mice aged. Credit: Nature 588(7836):124-129.

Good Cells Can’t Drive Out Bad

And there are even narrowly cellular forms of aging damage that you can’t or wouldn’t want to “repair” using reprogramming. Yes, you can reverse cellular senescence by reprogramming, and with a few additional tricks you can even reverse reprogramming-induced senescence, but is that a good idea? Remember, the cellular senescence machinery is a kind of emergency brake, which the cell pulls when it is in danger of careening out of control, such as by progressing to become a cancer or by laying down excessive collagen after an injury, leading to fibrosis. Releasing the emergency brake (senescence) on such damaged vehicles (cells) sets it rolling again, making the body once again prone to a crash of one kind or another. (Instead, of course, the solution is to destroy senescent cells).

Indeed, some of these same scientists have previously shown that if they don’t get it quite right, in vivo reprogramming can cause cancers (as seen also here), presumably in some cases because reprogramming takes damaged non-cancerous cells further down the path toward becoming full-blown cancer. (It can also cause cellular changes that quickly kill the in vivo reprogrammed animals for reasons that are unlikely to be related to cancer). This is the main issue that most preoccupies scientists hoping to find a way to harness reprogramming for rejuvenation biotechnology. Fortunately, with some conscious work, there are a number of studies now where no major red flags have appeared — but that may be in part because all such studies have been too short-term for long-term side effects to emerge, and also in part the result of so few cells — and so few types of cells — actually being reprogrammed in these studies.

And reprogramming old but non-cancerous cells into more functional but still non-cancerous cells also isn’t likely to broadly drive out cancer existing, undiagnosed cancer cells, either. That said, an intriguing preliminary study suggest that in at least some cases, it might do something even more useful. In this study, scientists took pancreatic cancer cells from the tumors of pancreatic cancer patients and tried to reprogram them using three different protocols. None of these protocols was able to actually fully reprogram the cells as intended, but the cells that had been partially reprogrammed using their best protocol did display significant changes, including some that are associated with the reprogramming process.

To their own surprise, the researchers found that after this incomplete reprogramming, the cells looked and behave more like normal cells or stem cells in Petrie dish studies, and less like cancer cells. And when they implanted unmodified pancreatic cancer cells into mice, they formed tumors within 8–10 weeks, and all the mice died within three months — but partially-reprogrammed cells didn’t form any tumors within the same three-month study period.

Reprogramming pancreatic cancer cells taken from patients makes them far less likely to form tumors when implanted into mice. 247-Parental = unmodified cultured patient cancer cells. 247-REP = reprogrammed cells. Credit: Oncogene 38(34):6226-6239.

This was a small study, and it was with one particular cancer cell type tested under somewhat artificial conditions. And as we’ve already noted, in vivo reprogramming can cause cancers and abnormal tissue growths if scientists don’t get the dose, duration, and mix of reprogramming factors quite right. So it’s not implausible that the same reprogramming protocol could prevent some nascent cancers from erupting into full-blown disease, while nurturing a dark seed in others.

However this one issue pans out, when we look across the range of cellular and molecular aging damage that we need to remove, repair, or replace in order to free us from the specter of disease and death from aging, we need to spread our chips instead of putting them all into cellular reprogramming as a single inside bet.

A TAME Attempt to Slow Aging Part 2: Human Studies on Survival and Risk of Diabetes

Short summary: Metformin has been proposed as an “anti-aging drug,” and a major clinical trial is about to get underway to test the idea. In the first post in the series, we reviewed the animal data (especially lifespan studies) examining this question. In part two, we look at human studies on metformin in diabetes prevention and flawed observational studies that suggested that it reduced risk of diseases of aging and even increased life expectancy in nondiabetic people.

Human Studies: Compared to Whom?

The study that is most often cited as evidence that metformin slows the aging process in humans was released with a press release misleadingly titled “Type 2 diabetics can live longer than people without the disease.” But the underlying study[1] had a design flaw that first unintentionally selected only the healthiest diabetic patients (those on metformin) and compared them to patients with poorer glycemic control (those on other drugs) and a random assortment of the nondiabetic population — and then systematically pushed subjects on metformin “off the books” as soon as their diabetes progressed.[2],[3]

Because they wanted to compare people taking metformin to people who were not, the authors of the study removed subjects in the “metformin only” group from the analysis as soon as they started using additional diabetes medications. But diabetic patients are normally given metformin as their very first drug, with additional drugs being added on when the disease gets worse. By removing people who were initially taking just metformin from the analysis if they added on additional drugs during the course of the study, people whose diabetes got worse on metformin were systematically weeded out of the study.

But meanwhile, there was no such censoring of the other groups; consequently, when the study was over, the study scientists were comparing (a) an elite subset of people who began the study using metformin and continued to use it and no other diabetes drug group for an average of five additional years; (b) other diabetics who had worse disease and needed more intensive diabetes medication to control their diabetes from the outset; and (c) aging nondiabetics. So through a kind of methodological ratchet effect, the analysis only retained the healthiest metformin users, while people in the latter two groups remained in the study as they followed the normal trajectory of diabetic or aging people over time, getting sicker and sicker over the course of the study.[13],[14]

This way of analyzing the data accidentally thereby introduced a kind of survivorship bias into the study. As a result, the lower death rates in the metformin group as compared to the other two groups were in all likelihood the result of the design flaw in the study, not a special protective effect of the drug.[13],[14]

The same problem (or related ones) have plagued most of the observational studies that you may have heard cited as showing that metformin lowers the risk of atherosclerosis, total mortality, and especially cancer.

Drawing inferences from such studies about effects on aging in otherwise-healthy people would thus be misguided even if these studies didn’t share this design flaw, since none of these other studies include a separate group of people without diabetes. Rather, such studies have compared metformin-taking diabetic people to other people with diabetes taking other diabetic drugs. At best, such studies may imply that if you’re diabetic, it may be a better choice to milk as much as you can out of metformin before adding on injected insulin or drugs like sulfonylureas that push the body to release more insulin of its own.

But actually, even in such diabetics-only studies, the apparent benefits of metformin vanish when the studies are designed to avoid survivorship and selection bias.[4],[5],[6] Indeed, even in diabetic patients, actual clinical trials (as opposed to observational studies) find that metformin is no better than other diabetes drugs at preventing or slowing the course of cardiovascular disease.[7]

TAME: The Prequels Suck

In the midst of all the hype about TAME, it’s surprising how little attention has been afforded to the fact that a significant number of clinical trials testing metformin in nondiabetic, aging humans have already been done! And consistent with the rodent lifespan studies, these trials suggest that TAME is “not the anti-aging drug you’re looking for,” any more than Star Wars fans’ pent-up demand for new adventures with their heroes were fulfilled by Jar Jar Binks.

Credit: Star Wars: Age of Republic Special #1, c/o thathashtagshow.com

When put to the test in human trials, metformin has no effect on blood sugar control in obese women with normal glucose tolerance[8] and only modest effects on fasting glucose in normal-weight, nondiabetic men.[9] Even in people who are on the path to diabetes, decidedly non-heroic exercise programs with modest dietary improvement outperform metformin at holding off the development of the full-blown disease.[10],[11],[12] In such prediabetic people, such a minimal lifestyle intervention is also more effective than metformin at lowering cardiovascular risk factors without the use of specific medications like statins or blood pressure drugs.[13] Similarly, exercise but not metformin tames glycemic variability (dangerously wide swings in blood sugar over the course of the day) in prediabetic people.[14]

And importantly, adding metformin to such lifestyle interventions doesn’t lower the risk of developing diabetes any more than lifestyle all by itself.[21],[22] Similarly, while both exercise and metformin do each improve a number of metabolic risk factors for cardiovascular disease, combining the two confers no further benefit.[15] In fact, most (though not all[16]) studies have found that taking metformin actually blunts the beneficial fitness and metabolic adaptations to both aerobic[15],[17],[18] and strength-training exercise[15],[19],[20] in older or prediabetic adults (see also the more preliminary studies reviewed in reference (21).

These were all short-term studies — but we do have long-term data from the followup of a large randomized controlled trial of the effects of metformin on frailty in aging people with prediabetes.  When researchers followed up 12-14 years later, people who been randomized to take a sugar pill along with moderate diet and lifestyle reforms cut their risk of becoming frail in the next ten years by nearly 40% as compared to people taking a placebo but who were not assigned a lifestyle intervention. But those who were given real metformin tablets without a lifestyle intervention did no better than the controls — even though for much of the remaining time, they could opt in to the lifestyle program.[23]

And similar to its apparent effects on exercise gains, metformin may also blunt some of the benefits of a healthy diet, as we’ll discuss in Part 4 of this series. So far from being one more tool in the toolbox that an otherwise-healthy aging person draw upon to further their healthy-lifestyle efforts to stave off secondary aging, metformin appears to actually get in the way of people realizing those gains.

A TAME Spoiler?

In Part 1 of this series, we saw that metformin repeatedly failed to extend life in well-designed rodent studies. And as we’ve discussed above, a study trumpeted as showing that people with diabetes taking metformin live longer than people without diabetes not taking the drug was the product of a faulty design. TAME will not be directly testing the effect of metformin on lifespan, for reasons we’ll discuss in Part 5 of this series, but you may be surprised to learn that there has already been a trial with followup that gives fairly long-term human data on mortality in a group of people who were not yet diabetic — and again, metformin came up short.

This was report from the long-term follow-up of the Diabetes Prevention Program (DPP), a randomized controlled clinical trial that included more people than will be used in TAME (3,234 volunteers). The volunteers in the DPP were on average 50 years old, and all had prediabetes, which made them more likely to benefit from metformin than are the people in TAME, who will be otherwise-healthy but suffering from degenerative aging.

Subjects in the DPP were divided randomly into three groups. One group was given metformin tablets, along with standard advice about healthy diet and exercise. Another group was given the same guidance, but a dummy pill instead. And a third group also received the dummy pill, but were also enrolled into a healthy lifestyle program (rather than just being given general guidelines). This was not an elite lifestyle medicine program with free superfoods and a personal physical trainer, but sessions where they were encouraged and guided to get 150 minutes of exercise per week (including walking) and practice the low-fat portion-control diet typical of health guidance in the 1980s and 90s, with the aim of a 7% loss of weight.

The DPP itself lasted only 2.8 years, but the researchers at the National Institute of Diabetes and Digestive and Kidney Diseases followed up with the participants at 10, 15, and as much as 20 years later. And to get to the punchline, people who had been taking metformin lived no longer than people in the control group.[24]

Over 20 years of followup from the DPP, people assigned to take metformin lived no longer than people taking a placebo.
Credit: Diabetes Care 44(12):2775-2782.

If metformin fails to slow aging enough to affect mortality rates over a 20-year period, as 50-year-old prediabetic people age out to become septuagenarians, how can it reasonably be expected to slow aging in people who don’t already have a good rationale for metformin as a way to address their prediabetes?

Metformin and the Heart

As with diabetes, a number of clinical trials have also tested metformin’s ability to protect cardiovascular health, and they have almost universally come back empty. The most important of these was the CAMERA trial, in which the same dose of metformin that will be used in the TAME trial was tested in a randomized, controlled trial in older people without diabetes, but with coronary heart disease. After a year and a half on the drug, atherosclerosis worsened at the same pace in people taking metformin as it did in people taking the placebo.[24]

In the GIPS-III trial, nondiabetic patients who had suffered a heart attack and had had a stent placed in their coronary artery were then given either metformin or a placebo, at random. This was prompted by animal studies in which the hearts of mice given simulated heart attacks recovered better if the mice were given metformin afterward. But in the human trial, people who received metformin were no less likely to suffer loss of heart-pumping effectiveness than people receiving a placebo.[25]  Their hearts also suffered no less damage,[26] and over the course of the two years following their original heart attack, the metformin-treated subjects suffered just as many new heart attacks as did placebo-treated controls.[27]

Another small trial that gave people with prediabetes who didn’t already have CVD either metformin or a placebo had similar results. While metformin had some very small effects on different blood tests, it had no effect at all on actual cardiovascular events like heart attacks and strokes, and didn’t improve quality of life.[28] The same basic upshot also emerged in an earlier meta-analysis of clinical trials on the effects of metformin on cardiovascular disease that mostly included people with diabetes, but also included some nondiabetics.[29] Indeed, as we noted earlier, even in people who do have diabetes, clinical trials find that metformin is no better at preventing or slowing the course of cardiovascular disease than other diabetes drugs.[18]

Credit: Shutterstock

We should get an even more definitive answer on whether metformin protects cardiovascular health in aging but nondiabetic people long before TAME is complete, thanks to the VA-IMPACT trial. With 3000 subjects being enrolled, VA-IMPACT will be the largest trial of metformin in nondiabetic people other than TAME itself. The earlier CAMERA trial[22] monitored the effect (or, as it turned out, lack of effect) of metformin on the progression of atherosclerotic lesions in the volunteers’ arteries, but didn’t last long enough or have enough subjects to confidently rule in or out an effect on more life-changing cardiovascular outcomes like heart attacks and strokes. VA-IMPACT will use its size and duration to answer that exact question.

But I wouldn’t hold my breath. It’s certainly true that some smaller or less-controlled trials have reported effects on different cardiovascular outcomes, but the best available evidence seems to fairly clearly rule out a substantial protective effect of metformin against cardiovascular disease in nondiabetic people.

Probably the reports about purported benefits of metformin in people without diabetes that have garnered the most interest from people outside of prolongevists have been those that suggested it might prevent or treat cancer. That evidence, too, has been followed up into the gold standard test of human clinical trials in nondiabetic people — and here again, metformin has failed to live up to the misguided expectations. That’s the subject of the next post in this series.

Citations:

[1] Bannister CA, Holden SE, Jenkins-Jones S, Morgan CL, Halcox JP, Schernthaner G, Mukherjee J, Currie CJ. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes Metab. 2014 Nov;16(11):1165-73. doi: 10.1111/dom.12354. Epub 2014 Jul 31. PMID: 25041462.

[2] McConway K. Expert reaction to study looking at type 2 diabetes, metformin and lifespan. Science Media Centre. 2014 Aug 8. Online resource: http://www.sciencemediacentre.org/expert-reaction-to-study-looking-at-type-2-diabetes-metformin-and-lifespan/ . Accessed 2022-06-22.

[3] Margulis MV, Pladevall M, Riera-Guardia N, Seeger J, Patorno E, Varas-Lorenzo C. Comment on: Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. PubPeer. 2016 Mar. Online resource: https://pubpeer.com/publications/4E29C6C9E32D2C24662AED78A59AC5 Accessed 2022-06-22.

[4] Farmer RE, Ford D, Mathur R, Chaturvedi N, Kaplan R, Smeeth L, Bhaskaran K. Metformin use and risk of cancer in patients with type 2 diabetes: a cohort study of primary care records using inverse probability weighting of marginal structural models. Int J Epidemiol. 2019 Apr 1;48(2):527-537. doi: 10.1093/ije/dyz005. PMID: 30753459; PMCID: PMC6469299.

[5] Tsilidis KK, Capothanassi D, Allen NE, Rizos EC, Lopez DS, van Veldhoven K, Sacerdote C, Ashby D, Vineis P, Tzoulaki I, Ioannidis JP. Metformin does not affect cancer risk: a cohort study in the U.K. Clinical Practice Research Datalink analyzed like an intention-to-treat trial. Diabetes Care. 2014 Sep;37(9):2522-32. doi: 10.2337/dc14-0584. Epub 2014 Jun 4. PMID: 24898303.

[6] Stevens RJ, Ali R, Bankhead CR, Bethel MA, Cairns BJ, Camisasca RP, Crowe FL, Farmer AJ, Harrison S, Hirst JA, Home P, Kahn SE, McLellan JH, Perera R, Plüddemann A, Ramachandran A, Roberts NW, Rose PW, Schweizer A, Viberti G, Holman RR. Cancer outcomes and all-cause mortality in adults allocated to metformin: systematic review and collaborative meta-analysis of randomised clinical trials. Diabetologia. 2012 Oct;55(10):2593-2603. doi: 10.1007/s00125-012-2653-7. Epub 2012 Aug 10. Erratum in: Diabetologia. 2012 Dec;55(12):3399-400. PMID: 22875195.

[7] Griffin SJ, Leaver JK, Irving GJ. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia. 2017 Sep;60(9):1620-1629. doi: 10.1007/s00125-017-4337-9. Epub 2017 Aug 2. PMID: 28770324; PMCID: PMC5552849.

[8] Binnert C, Seematter G, Tappy L, Giusti V. Effect of metformin on insulin sensitivity and insulin secretion in female obese patients with normal glucose tolerance. Diabetes Metab. 2003 Apr;29(2 Pt 1):125-32. PubMed PMID: 12746632.

[9] Fruehwald-Schultes B, Oltmanns KM, Toschek B, Sopke S, Kern W, Born J, Fehm HL, Peters A. Short-term treatment with metformin decreases serum leptin concentration without affecting body weight and body fat content in normal-weight healthy men. Metabolism. 2002 Apr;51(4):531-6. PubMed PMID: 11912566.

[10] Diabetes Prevention Program Research Group, Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ, Brenneman AT, Brown-Friday JO, Goldberg R, Venditti E, Nathan DM. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009 Nov 14;374(9702):1677-86. doi: 10.1016/S0140-6736(09)61457-4. Epub 2009 Oct 29. Erratum in: Lancet. 2009 Dec 19;374(9707):2054. PubMed PMID: 19878986; PubMed Central PMCID: PMC3135022.

[11] Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V; Indian Diabetes Prevention Programme (IDPP). The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia. 2006 Feb;49(2):289-97. Epub 2006 Jan 4. PubMed PMID: 16391903.

[12] O’Brien MJ, Perez A, Scanlan AB, Alos VA, Whitaker RC, Foster GD, Ackermann RT, Ciolino JD, Homko C. PREVENT-DM Comparative Effectiveness Trial of Lifestyle Intervention and Metformin. Am J Prev Med. 2017 Jun;52(6):788-797. doi: 10.1016/j.amepre.2017.01.008. Epub 2017 Feb 22. PMID: 28237635; PMCID: PMC5438762.

[13] Diabetes Prevention Program Outcomes Study Research Group, Orchard TJ, Temprosa M, Barrett-Connor E, Fowler SE, Goldberg RB, Mather KJ, Marcovina SM, Montez M, Ratner RE, Saudek CD, Sherif H, Watson KE. Long-term effects of the Diabetes Prevention Program interventions on cardiovascular risk factors: a report from the DPP Outcomes Study. Diabet Med. 2013 Jan;30(1):46-55. doi: 10.1111/j.1464-5491.2012.03750.x. PubMed PMID: 22812594; PubMed Central PMCID: PMC3524372.

[14] Færch K, Blond MB, Bruhn L, Amadid H, Vistisen D, Clemmensen KKB, Vainø CTR, Pedersen C, Tvermosegaard M, Dejgaard TF, Karstoft K, Ried-Larsen M, Persson F, Jørgensen ME. The effects of dapagliflozin, metformin or exercise on glycaemic variability in overweight or obese individuals with prediabetes (the PRE-D Trial): a multi-arm, randomised, controlled trial. Diabetologia. 2021 Jan;64(1):42-55. doi: 10.1007/s00125-020-05306-1. Epub 2020 Oct 16. PMID: 33064182.

[15] Malin SK, Nightingale J, Choi SE, Chipkin SR, Braun B. Metformin modifies the exercise training effects on risk factors for cardiovascular disease in impaired glucose tolerant adults. Obesity (Silver Spring). 2013 Jan;21(1):93-100. doi: 10.1002/oby.20235. PMID: 23505172; PMCID: PMC3499683.

[16] Pilmark NS, Oberholzer L, Halling JF, Kristensen JM, Bønding CP, Elkjær I, Lyngbæk M, Elster G, Siebenmann C, Holm NFR, Birk JB, Larsen EL, Lundby AM, Wojtaszewski J, Pilegaard H, Poulsen HE, Pedersen BK, Hansen KB, Karstoft K. Skeletal muscle adaptations to exercise are not influenced by metformin treatment in humans: secondary analyses of 2 randomized, clinical trials. Appl Physiol Nutr Metab. 2022 Mar;47(3):309-320. doi: 10.1139/apnm-2021-0194. Epub 2021 Nov 16. PMID: 34784247.

[17] Moreno-Cabañas A, Morales-Palomo F, Alvarez-Jimenez L, Ortega JF, Mora-Rodriguez R. Effects of chronic metformin treatment on training adaptations in men and women with hyperglycemia: A prospective study. Obesity (Silver Spring). 2022 Jun;30(6):1219-1230. doi: 10.1002/oby.23410. Epub 2022 May 17. PMID: 35578807.

[18] Konopka AR, Laurin JL, Schoenberg HM, Reid JJ, Castor WM, Wolff CA, Musci RV, Safairad OD, Linden MA, Biela LM, Bailey SM, Hamilton KL, Miller BF. Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell. 2019 Feb;18(1):e12880. doi: 10.1111/acel.12880. Epub 2018 Dec 11. PMID: 30548390; PMCID: PMC6351883.

[19] Long DE, Peck BD, Tuggle SC, Villasante Tezanos AG, Windham ST, Bamman MM, Kern PA, Peterson CA, Walton RG. Associations of muscle lipid content with physical function and resistance training outcomes in older adults: altered responses with metformin. Geroscience. 2021 Apr;43(2):629-644. doi: 10.1007/s11357-020-00315-9. Epub 2021 Jan 18. PMID: 33462708; PMCID: PMC8110673.

[20] Walton RG, Dungan CM, Long DE, Tuggle SC, Kosmac K, Peck BD, Bush HM, Villasante Tezanos AG, McGwin G, Windham ST, Ovalle F, Bamman MM, Kern PA, Peterson CA. Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double-blind, placebo-controlled, multicenter trial: The MASTERS trial. Aging Cell. 2019 Dec;18(6):e13039. doi: 10.1111/acel.13039. Epub 2019 Sep 26. Erratum in: Aging Cell. 2020 Mar;19(3):e13098. PMID: 31557380; PMCID: PMC6826125.

[21] Malin SK, Braun B. Impact of Metformin on Exercise-Induced Metabolic Adaptations to Lower Type 2 Diabetes Risk. Exerc Sport Sci Rev. 2016 Jan;44(1):4-11. doi: 10.1249/JES.0000000000000070. PMID: 26583801.

[22] Preiss D, Lloyd SM, Ford I, McMurray JJ, Holman RR, Welsh P, Fisher M, Packard CJ, Sattar N. Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trial. Lancet Diabetes Endocrinol. 2014 Feb;2(2):116-24. doi: 10.1016/S2213-8587(13)70152-9. Epub 2013 Nov 7. PubMed PMID: 24622715.

[23] Hazuda HP, Pan Q, Florez H, Luchsinger JA, Crandall JP, Venditti EM, Golden SH, Kriska AM, Bray GA. Association of Intensive Lifestyle and Metformin Interventions With Frailty in the Diabetes Prevention Program Outcomes Study. J Gerontol A Biol Sci Med Sci. 2021 Apr 30;76(5):929-936. doi: 10.1093/gerona/glaa295. PMID: 33428709; PMCID: PMC8087265.

[24] Lee CG, Heckman-Stoddard B, Dabelea D, Gadde KM, Ehrmann D, Ford L, Prorok P, Boyko EJ, Pi-Sunyer X, Wallia A, Knowler WC, Crandall JP, Temprosa M; Diabetes Prevention Program Research Group; Diabetes Prevention Program Research Group:. Effect of Metformin and Lifestyle Interventions on Mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study. Diabetes Care. 2021 Dec;44(12):2775-2782. doi: 10.2337/dc21-1046. Epub 2021 Oct 25. PMID: 34697033; PMCID: PMC8669534.

[25] Lexis CP, van der Horst IC, Lipsic E, Wieringa WG, de Boer RA, van den Heuvel AF, van der Werf HW, Schurer RA, Pundziute G, Tan ES, Nieuwland W, Willemsen HM, Dorhout B, Molmans BH, van der Horst-Schrivers AN, Wolffenbuttel BH, ter Horst GJ, van Rossum AC, Tijssen JG, Hillege HL, de Smet BJ, van der Harst P, van Veldhuisen DJ; GIPS-III Investigators. Effect of metformin on left ventricular function after acute myocardial infarction in patients without diabetes: the GIPS-III randomized clinical trial. JAMA. 2014 Apr 16;311(15):1526-35. doi: 10.1001/jama.2014.3315. PMID: 24687169.

[26] Lexis CP, Wieringa WG, van der Horst IC, Willemsen HM, de Smet BJ, van den Heuvel AF, van Veldhuisen DJ, van der Horst IC, Lipsic E, van der Harst P; GIPS-III Investigators. Effect of metformin on myocardial infarct size in patients without diabetes presenting with acute myocardial infarction: data from the Glycometabolic Intervention as adjunct to Primary coronary Intervention In St Elevation Myocardial Infarction (GIPS-III) trial. Submitted. Online resource: https://pure.rug.nl/ws/portalfiles/portal/19453050/Complete_dissertation.pdf#page=44 Accessed 2022-06-30.

[27] Hartman MHT, Prins JKB, Schurer RAJ, Lipsic E, Lexis CPH, van der Horst-Schrivers ANA, van Veldhuisen DJ, van der Horst ICC, van der Harst P. Two-year follow-up of 4 months metformin treatment vs. placebo in ST-elevation myocardial infarction: data from the GIPS-III RCT. Clin Res Cardiol. 2017 Dec;106(12):939-946. doi: 10.1007/s00392-017-1140-z. Epub 2017 Jul 28. PMID: 28755285; PMCID: PMC5696505.

[28] Griffin SJ, Bethel MA, Holman RR, Khunti K, Wareham N, Brierley G, Davies M, Dymond A, Eichenberger R, Evans P, Gray A, Greaves C, Harrington K, Hitman G, Irving G, Lessels S, Millward A, Petrie JR, Rutter M, Sampson M, Sattar N, Sharp S. Metformin in non-diabetic hyperglycaemia: the GLINT feasibility RCT. Health Technol Assess. 2018 Apr;22(18):1-64. doi: 10.3310/hta22180. PMID: 29652246; PMCID: PMC5925436.

[29] Lamanna C, Monami M, Marchionni N, Mannucci E. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2011 Mar;13(3):221-8. doi: 10.1111/j.1463-1326.2010.01349.x. PMID: 21205121.

Will SENS Benefit Progeria Patients?

SENSible Question: I just saw a news story about children with progeria. Their fate is terrible. Will SENS therapies help these children?

Short Summary:

A supporter asks if SENS rejuvenation biotechnologies will benefit patients with progerias — so-called “premature aging” diseases. They could — in part directly, and also by applying the same “damage-repair” principles to aspects of these diseases that are unrelated to aging and thus not the subject of SENS therapies. But much simpler ways to prevent these diseases entirely are also coming from gene therapy, for which there is no analogy in longevity therapeutics.

When people ask this question (as they often do), it’s usually premised on the reasoning that since these diseases are accelerated forms of the “normal” degenerative aging process that all humans suffer, SENS rejuvenation biotechnologies should benefit chronologically young progeria patients just as they will stave off disease and debility in people who are chronologically old by today’s standards.

But the claim that disorders like Hutchinson-Gilford Progeria Syndrome (HGPS), Werner syndrome, Cockayne’s syndrome, and Néstor-Guillermo Progeria Syndrome are “premature aging” diseases is an inaccurate characterization, grounded in superficial resemblances and scientific question-begging. In fact, as we discussed in a previous blog post, these diseases are caused by inherited mutations that are only tangentially related to the drivers of “normal” aging.

They are called “premature aging” diseases because the defective genes cause victims to develop conditions and health problems that overlap with the aging process — but only partially, and often for different reasons at the cellular and molecular level. This is why they are often called “segmental progerias:” because their victims are struck with incomplete segments of the aging phenotype.

And conversely, people with these conditions also exhibit characteristics and health conditions not typical of aging people, such as the short stature and high-pitched voices in people with Werner Syndrome, or hip dislocations and “bird-like” faces in HGPS. One particularly notable example is the thymus. The thymus gland is responsible for “training” precursor cells to become mature T-cells, which are a key cell type involved in the body’s response to specific viruses and cancerous cells. Notoriously, the thymus gland atrophies during aging, the functional tissue replaced by fat cells and other non-functional tissue. But almost the exact opposite happens in HGPS patients: not only do their thymuses not degenerate any faster than children the same age, but some patients’ thymuses undergo abnormal growth as the disease progresses!

Still, ”damage-repair” rejuvenation biotechnologies might very well help these patients by removing, repairing, or replacing the subset of their cellular abnormalities that occur in their bodies and line up closely enough with forms of cellular and molecular aging damage targeted by SENS.

For instance, the high burden of what appear to be senescent cells in HGPS patients and mouse models is the result of a mutation in the gene for LMNA, whose encoded proteins are important structural components of the nuclear envelope. These mutations cause abnormalities in the nuclear envelope’s shape and stability, and reprogrammed cells derived from HGPS patient cells have some of the characteristics of senescent cells. However, it is not clear that they are true senescent cells, and indeed they show some evident differences; as of 2019, “a comprehensive evaluation of the distribution and extent of cellular senescence in these HGPS models is has yet to be performed”.

However, these differences in the reasons why HGPS patients accumulate more senescent cells, and even some of the differences in the characteristics of the cells in question, may not matter when it comes to applying rejuvenation biotechnologies to help people suffering with the disease. Remember, one of the key advantages of the “damage-repair” heuristic of SENS is that it targets cellular and molecular damage itself, regardless of the specific metabolic processes that lead up to it. No matter what causes a cell to become senescent or to trigger its own death; no matter what triggers a nuclear or mitochondrial gene mutation; no matter why a given protein is permanently damaged inside or outside the cell — regardless of origin, removing, repairing, or replacing such damaged structures in a way that restores the youthful structural integrity of a person’s tissues can only benefit a person’s tissue function and health. So even if the abnormal cells accumulating in HGPS patients’ bodies aren’t true senescent cells, there’s still every reason to expect these patients to benefit from destroying the aberrant cells.

This isn’t just a reasonable prediction from first principles: it has proof-of-concept. In an animal study, scientists destroyed large numbers of the senescent-like cells in the tissues of mice with the same mutation as HGPS patients engineered into their genome. Treatment with a senolytic drug alleviated several of their aging-like health problems, greatly lowering their severe inflammation, allowing them to gain weight more normally, and increasing their terribly short life expectancy.

Treatment with senolytic drugs modestly increases life expectancy in a mouse model of the HGPS progeria. Credit: Nat Commun 9(1):5435.

Even after senolytic treatment, however, these mice still aren’t nearly as healthy or as long-lived as normal mice. HGPS causes other abnormalities in non-“senescent” cells, and both these mice and HGPS patients are (remember) rapidly accumulating these abnormal cell while they are still actually developing children, who ought to be producing many more healthy cells on an ongoing basis to develop normally. This is quite unlike biological aging, where senescent cells rare until early midlife, at which point growth is long over and the body needs to produce a much smaller number of new cells in order to maintain the tissues they have against the more insidious loss of cells to senescence and other aging processes.

Therefore, if senolytic therapies are ever used in HGPS patients, it will be doubly important to pair removal of abnormal cells with replacing the lost cells with healthy, non-mutated cells. (At SRF, Dr. Hadi Rebbaa and coinvestigators are working on the early development of such a “remove-and-replace” strategy for physiological aging).

The other important thing to remember is that all of the so-called “premature aging” diseases are in one critical sense entirely different from aging, inasmuch as they are the result of a relatively simple, unitary problem: patients carry just one key mutation in their cells. As such, and profoundly unlike aging, these diseases can ultimately be prevented entirely by either screening embryos during IVF procedures (Preimplantation Genetic Testing (PGT)) or — as gene therapy advances — by correcting the defective gene during early development, as has already been done in HGPS model mice.

By contrast, real aging is the result of many different kinds of damage — and that damage accumulates as an unintended result of normal, healthy genes carrying out normal, life-sustaining metabolic processes that unfortunately inflict damage on previously healthy, non-mutated cells. In aging, there is no underlying mutation to fix, and we interfere with normal metabolic processes at our peril. So repairing the many different kinds of cellular and molecular aging damage is our best path to a future where we can live free of age-related ill-health.

A TAME Attempt to Slow Aging Part 1: Misunderstanding Metformin in Mice

Short summary: Metformin has been proposed as an “anti-aging drug,” and a major clinical trial is about to get underway to test the idea. There’s not much chance that metformin will turn out to slow the rate of aging in humans, but TAME may help pave the way to important future trials of longevity therapeutics. In Part One of this four-part series, we’ll look at the animal studies that got many scientists excited about metformin in the first place and see where they went wrong.

Knowledgeable sources have reportedly told the press that the well-funded longevity therapeutics nonprofit Hevolution Foundation has tentatively agreed to provide the last tranche of funding for the long-delayed Targeting Aging with Metformin (TAME) trial. TAME is a large-scale human trial to see if the cheap, safe diabetes drug metformin can slow aging in a cohort of several thousand aging but nondiabetic people across the United States. Update, October 2022: a spokesperson for Hevolution has recently cast that claim into doubt, telling the health science news site STAT that it has “not yet made any decisions” about funding any particular project or venture.

While undeniably meriting at least one out of three cheers, the implications of this decision for the future of longevity therapeutics are decidedly mixed. On the one hand, we can say with a high level of confidence that metformin is a poor candidate as an anti-aging therapy. But on the other, the trial itself may pave the way for better candidate longevity therapeutics in the future, if the prolongevist community can navigate the craters its likely crash landing will create.

Rush to Judgement

The notion that metformin might have anti-aging effects began with a series of studies in mice and rats who weren’t dying as a result of the degenerative aging process, but from mutations that made them prone to cancer.[1],[2] But the first study of metformin’s effects on otherwise-healthy aging rats found no effect on median or maximum lifespan.[3]

There were some reasons to be skeptical of the negative result, and hopes were raised by another study published around the same,[4] which time found that metformin was beneficial in a stock of mice that, although short-lived for the species, are certainly much better test animals than grossly abnormal, mutant mice. But the significance of that study was undermined by a followup study from the same scientific team, which tested metformin in adult and older mice.[5] In their first, positive-looking metformin study, the scientists began treating the mice with metformin immediately after weaning. (To think about this, imagine your reaction if your doctor advised you that to avoid the worst impacts of your diagnosis (aging), you should have started taking a potential longevity drug as a toddler and then kept it up throughout your life). When, in the follow-up study, the scientists gave the same dose of metformin to the same stock of mice, but only started doing so once the animals were either young or middle-aged adults.

When mice began treatment at nine months of age (the human equivalent of one’s early 30s), the scientists found that metformin had only a small effect on median survival — and no effect on maximum lifespan. And when they held off dosing the mice until they were 15 months old (human-equivalent age 50), the drug had no effect at all.[5] Plus, in this stock of mice, metformin quite substantially reduced the animals’ weight — which might well be the explanation for the slight increase in median survival in the young adult mice, and which doesn’t happen so dramatically in most mouse strains or in nearly any humans.

The animal study most often cited as evidence that metformin slows aging in lab mice[6]is no such evidence at all. The investigators tested two doses of metformin in healthy, wild-type, nonobese mice. At the lower of the two tested doses, metformin increased the animals’ mean survival by a paltry 4-6%, and had no effect on maximum lifespan, meaning that the drug prevented a small number of deaths during and before middle age, but had no effect on aging. And when the mice were given the higher dose of metformin, it actually shortened the animals’ lives![6]

Metformin very slightly increased median survival at a lower dose, but shortened life at the higher dose. Credit: Nat Commun 4:2192.

Moreover, even the “low” dose of metformin was already so high that the levels of drug in the animals’ serum and liver were “considerably higher than seen in the serum of diabetic patients treated with metformin [my emphasis]”.[6] So how would one realistically attempt to translate this into human use? Based on the levels of metformin to which the animals’ tissues were actually exposed, you’d need a much higher dose than is used by diabetic patients to get even a very small change in median life expectancy. But yet “high-dose” metformin shortens life. So how high is too high?

A recent study made an attempt to suss out that question, and came up short.[7] The researchers tested two doses of metformin in rats in late life — a time in current lifespans that is more analogous to the ages of the people who will be enrolled in TAME, and at which most people will be the most motivated to seek out a longevity therapeutic. One dose was the same as the lower dose that had increased mean life expectancy in the two-dose study; the other was higher than that, but substantially lower than the much higher dose that proved to be toxic in the earlier study. Neither dose had any effect on median or maximum lifespan.[7]

Failing the Gold Standard

The best animal study to test metformin as a potential anti-aging drug was conducted as part of the National Institute on Aging (NIA)’s Interventions Testing Program: a rigorous, systematic effort to test conventional “messing with megabolism” anti-aging agents. ITP studies are designed with several features that make them a better test than the great majority of studies of whether a potential longevity therapeutic actually works (in mice!).

First, each time the ITP tests a potential longevity therapeutic, the lifespan study is done not just once, but three times independently in parallel, with three separate cohorts of mice living out their lives at three independent research sites, cared for by three different groups of scientists. So a candidate longevity therapeutic that succeeds in the ITP program will have extended lifespan not in just one isolated lab, but by three labs independently, essentially eliminating the chance of a pure statistical fluke or a result that can’t be replicated. Second, ITP tests all candidate longevity therapeutics in a healthy, genetically-diverse mouse population, which better resembles the normal human population than the genetically homogenous mouse strains that have been the workmice of biomedical research, which may have genetic quirks that make successful results meaningless for most or all humans. And third, all three groups of scientists that run the ITP studies in parallel with each other have a lot of experience in running well-conducted lifespan studies, which greatly reduces the risk of garbage-in-garbage-out results like (say) the recent nothingburger with glycine and n-acetylcysteine.[8]

And when the ITP researchers put metformin to the test, the result was unambiguous.[9] It did not extend the lives of the mice at any site. It did not even cause the modest reduction in early deaths seen in the previous, widely-cited study.[6] Metformin simply has no effect at all on lifespan in normal, healthy mice.

Metformin failed to extend lifespan in the NIA’s Interventions Testing Program (ITP). Credit: Aging Cell 15(5):872-84

This strongly suggests that previous reports of life-extending effects of metformin were either due to random chance, or were because metformin had an effect on some metabolic quirk peculiar to the mouse strain in the study, or were the result of poor experimental design or the researchers’ lack of understanding of what it takes to keep mice alive and thriving for the course of their adult lives up to the usual limits of their lifespans.

Bad Medicine

Meanwhile, several studies that have reported that metformin is actually harmful to otherwise-healthy aging mice have never gotten the attention of the one overemphasized positive-looking paper — a paper that (remember) itself reported metformin to be toxic at the higher of two tested doses.[6] For example, one study found that when metformin is given to mice in late middle age, it worsens age-related heart degeneration and shortens the mice’s lives (although this colony of mice was already short-lived, despite having normal genetics).[10] The drug also turned down the expression of genes involved the production of cellular energy, which was reflected in the reduced availability of cellular energy in the mice’s hearts.

Meanwhile, metformin turned up the expression of genes involved with production of structural proteins (extracellular matrix (ECM)), which sounds good — except that excessive, disordered ECM (fibrosis) is one of the things that stiffens the aging heart, making it a less effective pump. And indeed, the metformin-treated mice in the study had worse fibrosis than animals not given the drug.[10] (For the record, however, another study — this one conducted in older rats instead of middle-aged mice — found that metformin had a beneficial effect on the heart, and while it still didn’t lengthen the animals’ lifespan, it at least didn’t shorten it).[7]

And don’t get me started on the sorry state of the scientific literature on metformin’s effects in worms, flies, and cells in a dish. Such studies form the basis for most of the claimed mechanisms by which some scientists argue that metformin should slow aging, such as activation of the low-energy sensor AMPK or suppressing the activity of Complex I of the mitochondrial electron transport chain. I won’t spend much time on these: if you’re really interested, have a look at an open-access review that digs deep into the microscopic weeds.[11] I will say in that the data are such a scattershot mess; that the doses used in many of these studies are laughingly unrealistic; and above all that looking at what a drug does to isolated cells or to organisms that don’t have arteries, develop cancer, or have skeletal systems is an even less reliable way to predict what it might do in humans than are studies in lab rodents. And even drugs that work in our fellow mammals have a greater than 90% fail rate when tested in the species of interest: we humans.

More than 90% of drugs that are safe and effective when tested in experimental animals ultimately fail in human testing. Credit: Redrawn by Anne Corwin from Nat Rev Drug Discov 3(8):711-5.

Citations:
[1] Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, Kovalenko IG, Poroshina TE, Semenchenko AV, Provinciali M, Re F, Franceschi C. Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol. 2005 Aug-Sep;40(8-9):685-93. doi: 10.1016/j.exger.2005.07.007. PMID: 16125352.

[2] Anisimov VN, Egormin PA, Bershtein LM, Zabezhinskii MA, Piskunova TS, Popovich IG, Semenchenko AV. Metformin decelerates aging and development of mammary tumors in HER-2/neu transgenic mice. Bull Exp Biol Med. 2005 Jun;139(6):721-3. doi: 10.1007/s10517-005-0389-9. PMID: 16224592.

[3] Smith DL Jr, Elam CF Jr, Mattison JA, Lane MA, Roth GS, Ingram DK, Allison DB. Metformin supplementation and life span in Fischer-344 rats. J Gerontol A Biol Sci Med Sci. 2010 May;65(5):468-74. doi: 10.1093/gerona/glq033. Epub 2010 Mar 19. PubMed PMID: 20304770; PubMed Central PMCID: PMC2854888.

[4] Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, Tyndyk ML, Yurova MV, Kovalenko IG, Poroshina TE, Semenchenko AV. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle. 2008 Sep 1;7(17):2769-73. doi: 10.4161/cc.7.17.6625. Epub 2008 Sep 11. PMID: 18728386.

[5] Anisimov VN, Berstein LM, Popovich IG, Zabezhinski MA, Egormin PA, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Kovalenko IG, Poroshina TE. If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice. Aging (Albany NY). 2011 Feb;3(2):148-57. doi: 10.18632/aging.100273. PMID: 21386129; PMCID: PMC3082009.

[6] Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192. doi: 10.1038/ncomms3192. PMID: 23900241; PMCID: PMC3736576.

[7] Herbst A, Hoang A, Kim C, Aiken JM, McKenzie D, Goldwater DS, Wanagat J. Metformin Treatment in Old Rats and Effects on Mitochondrial Integrity. Rejuvenation Res. 2021 Dec;24(6):434-440. doi: 10.1089/rej.2021.0052. PMID: 34779265; PMCID: PMC8742278.

[8] Kumar P, Osahon OW, Sekhar RV. GlyNAC (Glycine and N-Acetylcysteine) Supplementation in Mice Increases Length of Life by Correcting Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Abnormalities in Mitophagy and Nutrient Sensing, and Genomic Damage. Nutrients. 2022 Mar 7;14(5):1114. doi: 10.3390/nu14051114. PMID: 35268089; PMCID: PMC8912885.

[9] Strong R, Miller RA, Antebi A, Astle CM, Bogue M, Denzel MS, Fernandez E, Flurkey K, Hamilton KL, Lamming DW, Javors MA, de Magalhães JP, Martinez PA, McCord JM, Miller BF, Müller M, Nelson JF, Ndukum J, Rainger GE, Richardson A, Sabatini DM, Salmon AB, Simpkins JW, Steegenga WT, Nadon NL, Harrison DE. Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer. Aging Cell. 2016 Oct;15(5):872-84. doi: 10.1111/acel.12496. Epub 2016 Jun 16. PMID: 27312235; PMCID: PMC5013015.

[10] Zhu X, Shen W, Liu Z, Sheng S, Xiong W, He R, Zhang X, Ma L, Ju Z. Effect of Metformin on Cardiac Metabolism and Longevity in Aged Female Mice. Front Cell Dev Biol. 2021 Jan 26;8:626011. doi: 10.3389/fcell.2020.626011. PMID: 33585467; PMCID: PMC7877555.

[11] Mohammed I, Hollenberg MD, Ding H, Triggle CR. A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan. Front Endocrinol (Lausanne). 2021 Aug 5;12:718942. doi: 10.3389/fendo.2021.718942. PMID: 34421827; PMCID: PMC8374068.

So what do the human studies tell us? That’s the question we’ll dig into in Part Two of this series!

Does An Immune Role for Beta- Amyloid Create a Therapeutic Dilemma for SENS?

SENSible Question: Some scientists have reported that viruses, bacteria, and other pathogens may help drive Alzheimer’s and other neurodegenerative diseases, and that the body uses beta-amyloid protein to fight them off. So doesn’t that mean it’s a bad idea to remove Abeta from the brain?

This is an important question, not only because of what it tells us about the specific issue at hand, but because it gets to the heart of the SENS “damage-repair” approach to longevity therapeutics.

Abeta is of course the sticky protein whose aggregates accumulate in the aging brain — most prominently in the brains of people diagnosed with Alzheimer’s disease (AD), and less dramatically in other dementias of aging. In fact, even absence of specific “diseases” of aging, Abeta is strongly implicated in driving so-called “normal” age-related cognitive decline. Accordingly, Abeta is an important target for therapies that remove damaged proteins from the brain, and part of the suite of rejuvenation biotechnologies that will be needed to keep our minds sharp, clear, and curious throughout greatly-extended life expectancies.

But as the questioner says, there is also mounting and important evidence that infectious microbes may be one of the drivers of Alzheimer’s and other diagnosed neurodegenerative diseases of aging. There’s lots of “scene of the crime”-type evidence for this: most people over the age of 65 have viruses and other microbes in their brains, and the brains of people diagnosed with Alzheimer’s disease have disproportionately high burdens of bugs like oral Herpes virus (HSV), the gingivitis bacterium P. gingivitis, and even the microbes that drive Lyme disease and syphilis. HSV in particular is disproportionately found in areas of the brain with high burdens of Abeta plaque.

And in the last 5-10 years, scientists have begun reporting that these two seemingly-unrelated drivers of neurodegenerative brain aging — Abeta aggregates and infectious pathogens — are actually interconnected in a surprising way. Evidence has been mounting that Abeta may actually be an antimicrobial peptide (AMP) — one of a class of small proteins that are produced by humans and other living things, and that exert broad, potent activity against bacteria, viruses, and fungi.

Dr. Rudy Tanzi, who discovered the genes behind several kinds of genetically-driven neurological disorders, reported in 2016 that Abeta binds to structures on the surface of eight microbes that infect humans. Binding to these sites on microbial invaders triggers individual molecules of Abeta to stick together, forming aggregated structures that imprison the pathogens.

To see if this effect was enough to actually protect animals from infection, Tanzi’s team inserted genes into several different species of lab animals that caused them to Abeta (which most animals don’t do naturally). Sure enough, the ability to produce Abeta significantly protected the animals from different infectious pathogens.

Then, when Dr. Tanzi and colleagues intentionally infected the brains of a mouse model of AD with a species of Salmonella bacteria, Abeta molecules rapidly locked into place together, with the highest levels of aggregated Abeta deposits at the site of infection. They also showed that Abeta had similar activity in three-dimensional cultures of infected human neurons.

Caption: Oral herpes virus infection causes human induced neural stem in a 3D bioengineered brain model to produce Abeta. Credit: Sci Adv 6;6(19):eaay8828.

These and related findings by Dr. Tanzi and others led to a new model for the role of Abeta in the aging and AD brain. In this new model, brain neurons produce Abeta as a way to protect themselves from microbial assailants. When they come in contact with a pathogen, molecules of Abeta bind to the intruder, which triggers them to stick together into aggregates. Trapping the brain bugs in a sticky web allows Abeta to deactivate the microbial raiders, protecting the brain from infectious assault.

Recognizing the Jigsaw Picture

With this new model, a number of things that scientists have been reporting for years suddenly start to make sense. For one thing, it’s long been known that the complement system is activated in the early stages of Alzheimer’s disease. The complement system is a part of the innate immune system that directly destroys pathogens by tearing open their membranes, and it was already known to be activated by other AMPs. But scientists have repeatedly reported that Abeta can also activate the complement system, which seemed like a bizarre, perverse thing for it to do. But that’s exactly what Abeta would be expected to do if it were itself an AMP: unleash dormant complement proteins at the location where they have trapped the intruding microorganism to help them finish the enemy off.

The new model also explains why proteins that are part of the complement system are often found bound up with Abeta plaques in the brain. Since the plaque handcuffs the very microbes that set off Abeta aggregation in the first place, he complement proteins wind up at the same location because the microbes they’re attacking are located there.

If Abeta is an AMP, it also reframes the role of inflammation in the aging and AD brain, and the associated activation of brain-resident immune cells called microglia. Microglia are like the macrophages of the brain, gobbling up particulate matter, cellular debris, and other harmful materials in the brain — including, importantly, Abeta — and digesting it in their lysosomes. If we reframe Abeta as an AMP, then the above progression may be somewhat analogous to the interaction of senescent cells with the immune system. Microglia actually have receptors on their surfaces that cause them to spring into action when they get a whiff of activated complement proteins, and as we mentioned above, Abeta causes dormant complement protein precursors to be converted into their active forms. In the Abeta-as-AMP model, this becomes an elegant host defense system: Abeta is released, traps a marauding microbe in a self-aggregating web of proteins, and then activates complement to help finish off the enemy and to recruit microglia to clean up the battlefield.

Activated microglia clustered around cerebral Abeta plaque in a mouse model of AD. Credit: Acta Neuropathol 126(4):461-77.

This sequence protects the brain from these toxic materials in the short term — first from the infectious intruder, and then from Abeta itself. But after years of taking in more and more Abeta and other harmful material in the aging brain, microglia eventually undergo a sort of Jekyll-to-Hyde transition. No longer able to take on more damaging material, the microglia nonetheless continue to senselessly churn out inflammatory factors, and may even turn traitor, attacking the very brain that they exist to defend.

If You Want War, Prepare for Peace

So your question is: if Abeta is helping to protect the brain from the threat of infection, doesn’t that make it potentially counterproductive to remove Abeta from the brain? Wouldn’t you be effectively scuttling a key brain defense system, leaving the brain even more vulnerable to infectious assault and neurodegeneration?

Indeed we would be — if our strategy were to inhibit the production of Abeta. Indeed, with benefit of hindsight, that might explain the fate of the many failed drugs that were intended to treat or prevent AD in exactly this way.

A few such drugs failed in clinical trials for unrelated reasons — notably, some of them were toxic to the liver, skin, or other organs. And  Flurizan, which got further along than many of the drugs of this type, flopped because it failed to improve AD patients’ mental functioning, quality of life, or ability to take the most basic care of themselves.

But that’s the least of it. Most of the Abeta synthesis inhibitor drugs failed in clinical trials not because they merely didn’t work, but because they actually made cognitive function even worse in people with Alzheimer’s! This was true of verubecestat, lanabecestat, atabecestat, and most famously Eli Lilly’s semagacestat. In light of the new research about Abeta’s role in protecting the brain from microbial marauders, we are confronted with the possibility that part of the reason that these inhibitor drugs impaired cognitive function in people with AD might be that they were unwittingly disabling one of the brain’s critical self-protection systems.

Break the Eggs to Make the Omelet. But Clean Up the Pan.

But remember, inhibiting a metabolic function like the production of Abeta is exactly the kind of thing that SENS rejuvenation biotechnology never does! This is the key feature that sets the “damage-repair” approach to developing longevity therapeutics apart from the earlier “gerontological” (or, often now, “geroscience”) approach, as well as from the ultimately futile “risk factor management” approach that dominates current medical efforts to hold diseases of aging at bay.

Drugs that inhibit Abeta production are in fact classic examples of the “gerontological” approach. By stimulating or suppressing the metabolic processes that contribute to aging damage, “gerontological” therapies aim to dampen down the amount of damage that they produce (or, alternatively, ramp up processes that rectify the early, reversible steps leading from such processes to stable structural damage), and thus slow the accumulation of the damage that metabolic processes cause. By contrast, SENS rejuvenation biotechnologies are targeted directly at the damage itself, leaving the metabolic processes that produce it to proceed without interference — but cleaning up the ensuing damage before it accumulates to high enough levels to cause us harm.

“Gerontological” drugs inhibit the metabolic processes that generate aging damage; the SENS strategy is to leave metabolism alone, and remove aging damage directly. All credit to Dr. Aubrey de Grey.

One of the main reasons to favor the SENS approach is exactly because interfering with metabolic processes is risky, since all such processes are in one way or another essential to keeping us alive and healthy.  There is no “aging program:” evolution did not build Abeta or LDL particles or the senescence machinery into us as so many little time bombs designed to ensure that we suffer degenerative aging. Instead, aging happens because the processes that were evolved to keep us alive and healthy in the short term are messy, and leave behind cellular and molecular damage in our tissues that our bodies don’t fully repair. In the long term, that damage accumulates in our tissues to the point that it impairs the ability of those tissues to carry out their exquisitely-regulated, evolved function. The ensuing dysfunction of a specific tissue is exactly what doctors then diagnose as a particular “disease of aging.”

In this case, Abeta is produced in the short term as an emergency response to microbial marauders; microglia are then activated and recruited to clear the dead pathogens and aggregated proteins out of the brain so that they don’t cause us harm of a different sort. So long as this cycle is executed flawlessly, the brain remains protected from threats and sustains function. But none of these processes less than perfect, they leave behind a few microbes here … a few protein aggregates there … and a few dysregulated microglia in another corner.

Meanwhile, other aging processes make it increasingly difficult to close the loop on the cycle of releasing and aggregating Abeta, destroying pathogens, and recruiting microglia to clean up the battlefield afterward. For instance, damage to the protective barrier shielding the brain and an increasingly dysfunctional immune system with age allow increasing numbers of microbes to penetrate the brain. And as microglia take up more and more Abeta over time, their lysosomes become increasingly unable to process the waste being sent their way, similar to what happens in arterial macrophages in the development of atherosclerotic cardiovascular disease. As a result, more and more Abeta aggregates get left behind to increase brain inflammation and weaken the connections between brain cells, and microglia become increasingly dysfunctional, ultimately doing more harm in the brain than good.

The core of this is articulated by Dr. Tanzi himself:

Abeta first entraps and neutralizes invading pathogens in beta-amyloid. Abeta fibrillization drives neuroinflammatory pathways that help fight the infection and clear beta-amyloid/pathogen deposits. In AD, chronic activation of this pathway leads to sustained inflammation and neurodegeneration. …

In the antimicrobial protection model, the modality of Abeta’s pathophysiology is shifted from abnormal stochastic behavior toward dysregulated innate immune response. However, beta-amyloid deposition in AD still leads to neurodegeneration. Thus, the new model extends but remains broadly consistent with the Amyloid Cascade Hypothesis and overwhelming data showing the primacy of Abeta in AD pathology.

As usual, the SENS approach is to cut the Gordian knot by taking a “hands-off” approach to the regulation of Abeta production, complement proteins, and the other metabolic processes implicated in the brain’s attempts (sometimes misguided) to defend itself, and instead to directly remove Abeta aggregates after they’ve been formed.

Remember, Tanzi discovered that Abeta defends the brain against microbial invaders by forming aggregates that capture and neutralize them. Once they’ve already carried out the attack, the whole snarled-up mess — Abeta polymers, dead microbes, and complement proteins— serves no further purpose and can be toxic to the brain. So Abeta that is cleared out after becoming aggregated has already finished serving a useful purpose, and is mere battlefield rubble that must be safely swept away to help rebuild the neighborhood.

All the Damage, All the Time

A comprehensive damage-repair strategy to sustain brain function over time will involve more than just clearing out Abeta, of course. SENS Research Foundation scientists are working right now to develop rejuvenation biotechnologies that directly degrade aberrant tau inside of neurons, and we are funding work to replace lost brain neurons and reinforce neuronal circuits.

And in the coming months, we expect to be able to announce a new project that promises to tackle the apparent therapeutic dilemma posed by the Abeta-as-AMP model even more pre-emptively: by directly destroying viruses and bacteria in the brain, while holding Abeta in a safe “reserve” mode. This is again a case of attacking the actual damage in the aging body (in this case, brain microbes), which can be contrasted with the recent failure of Cortexyme’s Atuzaginstat and abandonment of the next-generation COR588 —drugs that were intended to block gingivitis bacteria from contributing AD by breaking up their toxic metabolites, but that didn’t address the pathogen that was releasing those toxins in the first place.

A full strategy for indefinite brain maintenance may also one day involve fortifying the lysosomes of microglia to greatly increase their ability to safely clear out Abeta and prevent them from becoming dysfunctional and “flipping” on the brain, attacking the neurons they exist to protect.

What we’re not going to do is interfere with the brain’s ability to produce Abeta in the first place, or prevent it from aggregating as some have proposed. This has been true from the beginning, and now we see in hindsight another reason why such “messing with metabolism” is ill-advised: these approaches would risk leaving microbes free to vandalize the aging brain unchecked.

It's Not a Bug — It’s a Feature

Similar kinds of therapeutic pitfalls ensnare scientific proposals to interfere with metabolic processing driving other kinds of aging damage. Take senescent cells. It’s very clear that the accumulation of senescent cells in our tissues over time drives aging and age-related disease. This has frequently tempted scientists to develop drugs that might prevent cells from becoming senescent. But cells don’t pull on their senescence-inducing fire alarms as a kind of perverse metabolic prank. The elaborate machinery that turns cells exists to perform essential functions as part of embryonic development, wound healing, and the preventing fibrosis after injury, and most importantly in shutting down replication of cells on the verge of becoming cancer. The problem is not cells becoming senescent in the first place, it’s that a subset of them persist and accumulate after that essential function has been completed.

Cells become senescent to serve important physiological functions, but they contribute to degenerative aging as they accumulate in the tissues with age. Credit: Br J Cancer 114(11):1180-4.

The solution to this problem is not to prevent cells from undergoing senescence: that would leave us vulnerable to unchecked cancer and fibrosis. Instead, the SENS approach is allow cells to undergo senescence when they need to — and then destroy senescent cells before they can accumulate to the point of doing us irrevocable harm.

Similarly, our cellular power plants (mitochondria) generate toxic free radicals due to the imperfection of the machinery that converts energy derived from food to cellular energy in the form of ATP. This causes the mitochondria to damage themselves, including causing large deletions in their DNA, which forces the cell into an alternative energy regime that promotes damage and aberrant signaling in surrounding cells. Some of the “gerontological” mindset have proposed using drugs to dissipate the gradient that keeps the cellular energy production machinery working at full capacity as a way to keep mitochondria from damaging themselves so much and perhaps hold off mutation for a little longer. SRF scientists are instead working on  to engineer backup copies of the mitochondrial genes, so that our mitochondria can continue to produce energy normally, even if they do inflict mutations on themselves.

And so on, whether it’s aggregates inside cells, or nuclear DNA mutations and stable epigenetic damage, or the loss of functional stem cells. The “damage-repair” approach allows metabolism to do its essential work, but severs the link between metabolism and pathology by cleaning up the damage afterward. This iterable approach will allow us to live free of age-related disease and debility — potentially indefinitely — without compromising what not only keeps us alive, but makes life worth living.

Correlation between SASP or senescent cell burden and any routinely measured inflammatory marker?

SENSible Question: Is there any established correlation between Senescence-Associated Secretory Phenotype (SASP) or senescent cell burden on one side and the measured hsCRP level or any other routinely measured inflammatory marker in an individual on the other side?

Unfortunately not. Scientists first started asking this question around the time of the first proof-of-concept of the value of destroying senescent cells, and initially hoped it would be a straightforward matter of simply measuring the levels of various SASP factors directly in the blood. While none of the components of the SASP are common blood tests like hsCRP, some commercial blood-testing labs do test for specific proteins that are part of the SASP, including interleukin-6 and tumor necrosis factor alpha (TNF-α).

Somewhat surprisingly, however, things did not turn out to be quite that simple, for reasons that aren’t entirely clear. Perhaps the SASP factors concentrate too locally around senescent cells to be easily picked up in the blood. Or perhaps it relates to the fact that none of the individual proteins and lipid derivatives released from senescent cells as part of the SASP are actually unique to senescent cells. Instead, all of the proteins that make up the witches’ brew of proteins that is the SASP are are repurposed growth factors, protein-degrading enzymes, and above all inflammatory signaling molecules that also produced by non-senescent cells in the body to do things like break down damaged muscle, recruit immune cells, remodel injured tissue, and so on. This might mean that the signal from true SASP factors is swamped out by the fact that those same factors are produced at relatively high levels in an aged person’s body for other reasons, in response to their high burden of aging damage.

And precisely because each individual SASP factor is produced by non-senescent cells for other purposes entirely, no one marker can be used as a reliable index of SASP production: the level of any given factor always reflects a mixture of SASP-related production and production for entirely different reasons. As such, measuring just one or even a few SASP factors in the blood and correlating that to the actual number of senescent cells in your body or the level of SASP they’re producing is likely a fool’s errand from the start.

Scientists can largely bypass all of these problems in animal experiments, as they can simply euthanize the animal, remove the relevant tissue, and test the cells for the expression of the genes for SASP factors or the concentration of SASP proteins in the fluid immediately surrounding the tissue. But of course, that’s not a method we can use for testing the level of SASP or senescent cells in humans. Again, because SASP-constituent proteins are present in tissues for reasons unrelated to senescent cells, scientists must collect data on several SASP factors at once in the same tissue — and compare them to the levels of the same factors in a relevant control animal.

Similar multi-component protocols are also commonly used to measure the burden of senescent cells in aging mice and in mouse models of diseases of aging. Alternatively, scientists can use transgenic animals engineered such that cells expressing one important regulator of senescence light up under light of the right wavelength. Again, we can’t use this test for humans, as we have not been thus engineered.

The cells of transgenic mice fluoresce when expressing the key senescence regulator p16. Credit: Dev Cell 31(6):722-33.

Trouble for Trials

This is annoying enough when you just want to know about the burden of SASP or senescent cells in your own body out of morbid curiosity. But it becomes a real problem once you start trying to develop “senolytic” drugs intended to destroy senescent cells to rejuvenate the body and prevent or reverse diseases of aging in humans. These technical challenges mean that today’s scientists and startups are working with senolytic therapies that they know work brilliantly in mice, but about whose senolytic potency they are in large part flying blind once they start testing them in humans.

A fairly remarkable example of this is the failed UNITY Biotechnology trial of their lead senolytic for osteoarthritis. From human studies, we know that people suffering with osteoarthritis are burdened with high numbers of senescent cells in their knee cartilage — but obviously, the doctors running the trial weren’t going to take before-and-after biopsies of already worn-down cartilage to see if the drug lowered senescent cell burden. Instead, they tried to pump fluid into the knee via a fine needle and then siphon off and evaluate any change in SASP factors in the fluid that came out the other end. But despite the inside chamber of the knee being a small, tightly-enclosed, presumably senescent-cell-packed space, they still couldn’t get a clear read on whether the SASP was better, worse, or unchanged after therapy. Gathering the same SASP factors out of a blood sample is even less likely to tell you anything about your senescence burden.

A reliable, noninvasive biomarker of senescent cell burden would therefore unlock the potential of the senolytic field. It would give scientists, startups, and investors more confidence in the early stages of human testing that candidate senolytic drugs could actually destroy substantial numbers of senescent cells in living humans, and not just in laboratory mice or human cells in a Petri dish. Being able to validate “target engagement” this way would facilitate clinical trials of senolytics, prevent costly late-stage failures, and de-risk companies for investors, encouraging more funding for companies with viable senolytic candidates. (Unlike generic “biomarkers of aging” such as epigenetic aging clocks, similar biomarkers that reflect the level of specific forms of cellular and molecular aging damage are also important to the development and clinical use of other rejuvenation biotechnologies).

Markers in the Making?

After ruling out the SASP factors themselves as markers of senescent cell burden, there remain a small number of potential candidates for either biomarkers for total senescent cell burden, or for the senolytic action of drugs and other ApoptoSENS therapies such as the engineered senescent cell killers we are working on at SENS Research Foundation. But I’m not confident in the usefulness of any of these candidates today, even if you wanted to gamble on the possibility that they’ll turn out to be reliable measures in humans.

Additionally, you had wanted a test that was readily available with routine blood test screening, and none of the candidates we’ll discuss here are nearly as easy to access as a blood lipid or thyroid hormone test.

 

A Not-So-suPAR Test

One potential test is the soluble form (suPAR) of urokinase-type plasminogen activator receptor (uPAR), which is released into the serum when it is cleaved off of its normal position on the surface of the cell. When present on the cell surface, uPAR is itself a tricky actor: signaling through the receptor promotes the breakdown of the support structures around the cells in a variety of conditions, including both wound healing and invasion by cancer cells. And when something binds to uPAR to activate it, suPAR is cleaved off and released into the local environment in the process — and some of it reaches the serum.

Since suPAR is also a constituent of the SASP, scientists at the Memorial Sloan Kettering Cancer Center wondered if it might function as a senescent cell biomarker. They noted that other researchers had reported that people with a range of diseases in which senescent cells play a prominent role have elevated uPAR and/or suPAR levels, including diabetes, osteoarthritis, and idiopathic pulmonary fibrosis (a terrible disease of the aging lung), and that suPAR is actually used as a severity biomarker in both diabetes and kidney disease. Although it’s only available for research purposes in the United States, there’s even a commercial test for suPAR geared toward using it as a biomarker for the progression of many of these diseases. It is furthermore known that suPAR levels rise with age, although the slope of the rise with age is gentle, the average varies considerably, and it ultimately tends to plateau.

suPAR levels tend to rise with age. Credit: Sci Rep 10: 15462.

Moving to the laboratory, the researchers found that both the number of uPAR-positive cells and serum suPAR levels increased in mice that were exposed to either chemotherapy drugs that work by forcing cancer cells into senescence, or to a liver toxin that also is known to raise the burden of senescent cells. They also found high levels of uPAR expression in fibrotic human livers that they separately confirmed to be loaded with high numbers of senescent cells, and in atherosclerotic plaques removed from human patients.

Unfortunately, there are a number of reasons to skeptical of the conclusion that suPAR could serve as a good biomarker for senescent cells or SASP. On the mousey side of the question, many of the key experiments in the mouse paper (which, so far, is the only study reporting suPAR as a senescent cell biomarker) used only 3 mice, or in one case 4, for each group, which is just too few animals on which to draw robust conclusions. Additionally, the investigators relied on just one independent senescence marker to confirm the correlation between senescent cell burden and uPAR or suPAR levels. This makes all their claims questionable, precisely because there is no single marker that can identify a cell as senescent. For this reason, it’s expected in the field that all claims about cells being senescent in general and senescent cell burden in particular will be confirmed by testing a sample for multiple senescence markers to confirm that they all line up.

Another problem, which is particularly important to developing longevity therapeutics, is that all the animal studies were actually conducted in young mice. These animals had (or were expected to have) high levels of senescent cells in their tissues not due to the tissue-ravaging effects of the degenerative aging process, but because they’d been subjected to insults that rapidly riddle one’s tissues with senescent cells, including a DNA-damaging chemotherapy drug, cancer-promoting genetic engineering, or being overfed to develop metabolic-associated fatty liver disease (MAFLD). Although the cells were still senescent, the context of that senescence — being in an otherwise-young body with one extreme source of senescence — might well make a suPAR signal clear in these artificial animal models but confounded or swamped out in otherwise-healthy aging humans.

Indeed, while the authors noted that suPAR levels are high in people suffering with a variety of diseases of aging in which senescent cells play a causal role, it’s also elevated in a lot of conditions that don’t seem likely to have such a connection, including many infectious diseases; pancreatitis; mental disorders such as depression, bipolar disease, and schizophrenia; and in young and middle-aged adults (though not people who are biologically old in our current condition) being female rather than male. That last one is notable given that females live longer than males across almost all mammalian species on which we have good information, and especially of human women vs. men. So if suPAR levels are a surrogate marker of senescent cells or SASP burden, why would even relatively young women have higher circulating suPAR?

The weaknesses of the animal evidence; the many diseases unrelated to aging with which elevated serum suPAR levels are associated; the gender paradox; and the fact people of similar ages show a wide range of suPAR levels and the rise with age shows such a gentle and plateauing slope (see the Figure above) compared to the sharp rise in disease and debility, all suggest that suPAR is not likely to be useful as a senescence biomarker.

Paradox in the Plasma

First things first: we’re talking about GDF-15, which is not to be confused with GDF11, the controversial serum factor purported by some to have regenerative effects in aging mice but which has been widely reported to have no such effects and even to cause tissue atrophy instead. GDF-15 is a member of a family of proteins often associated with both inflammation and tissue growth, and is elevated in many pathological conditions (including cancer and the immediate aftermath of a heart attack) and is particularly useful as a marker of inherited mitochondrial diseases.

More to our point, GDF-15 a nonclassical component of the SASP, and at more moderate levels is linked in many, many prospective studies to risk of multiple adverse age-related outcomes, and is a marker of age-related mitochondrial dysfunction as well as inherited mitochondrial disease. All of this seems like circumstantial evidence that elevated GDF-15 might be a biomarker for the SASP. Unfortunately, any such use is confounded by many other things that also elevate GDF-15 and are clearly not related to senescent cells or SASP. The most paradoxical of these is that GDF-15 levels are elevated both by the metabolic syndrome, and by the drug metformin, which of course is used to treat metabolic syndrome and diabetes.

Even more paradoxically, when metformin use leads to weight loss (which it does in some people), it actually seems to work by boosting GDF-15 levels in rodents and in humans. In fact, there’s evidence that the metabolic benefits of weight loss and exercise depend on GDF-15. Metformin and exercise both seem to increase the level of circulating GDF-15 by increasing the production of the stress-response protein ATF4 — which makes the GDDF-15 connection even more paradoxical, because multiple interventions that slow aging in mice also elevate ATF4, and there’s evidence that ATF4 is playing a causal role in the process.

Credit: Anne Corwin, SRF.

A plausible narrative would be that in all of these cases, GDF-15 is playing a role in responding and adapting to stressors including metformin, exercise, and these various anti-aging interventions; that’s consistent with GDF-15’s role in resolving inflammation. But then where does that leave GDF-15 as a marker of the (inflammatory) SASP? It may well do both (senescence is, after all, itself very stressful state for the cell), but then how do you tell which of these many reasons explains your high GDF-15 level, or even if you should be alarmed or relieved if your levels are high?

Smelling Blood

Although it’s not quite the kind of marker you were looking for and is the furthest from being readily available at a local blood lab, it’s also worth mentioning dihomo-15d-PGJ2 (d15P). This analyte is an eicosanoid (a signaling molecule derived from essential fatty acids) that appears to be uniquely produced inside senescent cells. It’s known that senescent cells undergo metabolic shifts that encourage the production of high levels of eicosanoids, and they do produce some specific fatty signaling molecules as part of the SASP.

But d15P is different: senescent cells produce this unusual lipid mediator, but then hold it inside themselves. It turns out that d15P plays a role in both pushing the cell into the senescent state, and keeping it there — and also in promoting many components of the SASP. This turns into a self-reinforcing cycle, in which d15P enforces senescence through the cell fate regulator p53 — but then p53 promotes the production of a critical enzyme involved in eicosanoid synthesis, which sustains the production of d15P.

Senescence and d15P production reinforce each other. Credit: Cell Metab 33(6):1124-1136.e5.

But, you ask, if almost all of a senescent cell’s d15P remains trapped inside of it, how can d15P be used as a blood biomarker for the SASP? The answer is: it can’t. But it can be used as a marker of senolysis: the destruction of senescent cells, through senolytic drugs or engineered senescent cell-killing immune cells.

In the paper reporting these results, the scientists showed that destroying cultured senescent cells with senolytic drugs in a dish causes them to flood the culture medium with d15P, whereas d15P is absent from the medium after destroying non-senescent cells with drugs that induce cellular suicide indiscriminately in all cells. They also confirmed the effect in mice with a high burden of senescent cells. Following administration of senolytic drugs to these mice, d15P levels rose to high levels in their urine and blood in the hours after their senescent cells started to die off. By contrast, no d15P appeared in the fluids of mice with low (young) levels of senescent cells even after the senolytic drug was administered, and or when mice with a high senescent cell burden were given a “placebo” instead of a senolytic drug.

In the near term, a marker that scientists could use to confirm that a potential senolytic drug is actually killing senescent cells in an aging or ill person would be incredibly useful for longevity therapeutics companies working in the senolytic space. Such a marker would enable them to verify that their drugs actually work in people, not just in mice or cells in a dish. That would save a significant amount of potentially wasted money, and also give initial evidence of efficacy – factors with enormous potential to entice major investments from well-financed venture capital firms or Big Pharmas. Then, once these drugs reach the market, the marker would allow future longevity doctors to confirm that their patients were actually benefitting from taking the drugs, and help them decide how often they would need to repeat the therapy.

Unfortunately, like the other potential biomarkers, d15P has some limitations. One is how little work scientists have done to confirm that d15P is a useful senolysis marker under conditions reflecting those used in clinical trials and in medical practice. The mouse studies described above induced senescence by ravaging the bodies of young mice with a senescence-promoting chemotherapy drug, not by testing senolytic drugs in mice with high levels of senescent cells due to aging or disease. A separate study that used d15P to confirm the senolytic effect of a potential senolytic metabolite similarly conducted their test after inducing high levels of senescence in young mice.

Additionally, while many studies show that both suPAR and GDF-15 levels are elevated in people with conditions where senescent cells are implicated, there are no in vivo human data for d15P: nearly everything we know about it comes from these limited cell and mouse studies.

And while it’s difficult to get a person’s suPAR or GDF-15 levels measured, there are at least specialized laboratories that offer the service for human use in scientific studies. By contrast, there is no test even validated to measure d15P in human plasma. Furthermore, in the d15P paper they initially measured d15P using an antibody-based technology that underlies many common laboratory tests. However, the antibody on which this test relies is not specific to d15P, and required the researchers to confirm key results using an additional backup test that requires the more specialized mass spectrometry method. The scientists involved also highlight how understudied d15P is compared to other eicosanoids, and the sheer finickiness of the assay.

So before d15P gets put into human use, a specialized laboratory will first have to develop such a test. And because it would be the first of its kind, there’s not yet a standard against which to validate such a novel test. And since everyone over the age of 30 or so has some non-trivial number of senescent cells, to give meaningful information about how much senolytic impact a given level of d15P represents would require extensive testing in a wide range of people of different ages and with various senescence-linked diseases. Without that additional information, it’s impossible to know whether a given level of d15P following administration of a senolytic means you’ve cleared out an enormous burden of senescent cells, or a few such cells unlucky enough to be vulnerable to a minimally-effective drug.

Navigating by the Stars

As we’ve seen, there’s no reliable marker available for SASP, senescent cells, or successful senolysis — let alone a readily-available lab test that you could expect a health insurer to cover as part of your care. That might leave you feeling that you’re left sailing blind into the sea of your own aging — as, unfortunately, we all by and large are.

But there is some light from the stars by which we can navigate our way home. While we await the availability of biomarkers of senescence, we do know about some important ways to avoid worsening our burden of senescent cells, whatever it may be: not smoking, consuming moderate or no alcohol and other contributors to liver fibrosis, and maintaining a healthily low level of body fat.

And by promoting, funding, and advancing rejuvenation research, we can help steer our ship out of the storm. In the coming safe harbor, our old timbers can be replaced, our hulls scraped clean of barnacles, and our sails mended good as new.

New Peer-Reviewed Paper from SENS Research Foundation Reports a Better Method to Study How Immune Cells Seek and Destroy Senescent Cells

Senolytics — drugs that selectively destroy senescent cells (senolytics) — have been shown to powerfully rejuvenate mice and to reverse multiple diseases of aging in animals, from atherosclerosis, to kidney disease, to osteoporosis, to Parkinson’s disease — and beyond. But because these drugs target pathways that are necessary for normal cell function, they can come with side-effects — the most notable being the crash in platelets (and resulting risk of fatal bleeds or strokes) that can accompany the experimental senolytic navitoclax.

But our bodies are actually equipped with an inborn army of immune cells that selectively identify and destroy senescent cells. To date, the most important of these “immunosenolytic” cells soldiers have seemed to be Natural Killer cells (NK cells) — though we will have an announcement to make on this front in the coming months. But if the body already has this defensive force, how do senescent cells still manage to accumulate in our tissues with age and wreak havoc on our health?

As part of SENS Research Foundation’s work to eradicate dysfunctional cells driving aging (ApoptoSENS), Dr. Amit Sharma and his team at SRF are developing ways to either rejuvenate our own NK cells’ ability to detect and destroy senescent cells in aging tissues, or to augment that capacity with NK cells engineered to be more lethal senescent cell hunters. To reach those goals, they realized they needed a more efficient way to enrich NK cells from mixed white blood cells isolated from human blood. In new peer-reviewed scientific paper, they show how they did it.

Their main innovation might seem to be an obvious one: to actually isolate NK cells and activate them to better mimic the situation in vivo. Previous studies have mostly used mixed populations of blood cells, sometimes removing T-cells or other specific cell types but never ensuring that they had isolated NK cells exclusively. Dr. Sharma used an existing kit to make sure that what they were seeing came from the NK cells and not from other cell types.

They also saw that the way that previous researchers had studied NK cells’ ability to destroy senescent cells was quite different from the conditions NK cells actually confront as they patrol for NK cells in the body, potentially leading scientists to chase after interventions that work well in a Petri dish but have no effect or are unsafe when carried out in living, breathing humans. This is probably because most scientists conducting these studies don’t have a specialized background in immunology: instead, they design their experiments based on a general background in the biology of aging or cancer biology, or as specialists in senescence per se, but

The biggest problem the SRF group corrected is that previous studies have cultured low numbers of senescent cells together with very high numbers of NK cells, creating a situation where NK cells are effectively shooting zombie fish in a barrel. Dr. Sharma’s team tested more realistic conditions in which one NK cell encounters one senescent cell, or no more than three, instead of ratios as high as one senescent cell target to 20 or even 80 NK cells.

Conversely, having given NK cells so many senescent cell targets that they can hardly fail to kill some, most previous studies have only set NK cells loose for a few hours, when NK cells have a half-life in the body of ten hours. So the ApoptoSENS team led by Dr. Sharma gave NK cells more time to engage their enemies, which better reflects how long they actually hang out in tissues, with experiments running from 16 hours to four days. This also gives the NK cells the ability to reveal their full range of powers, since some of their cell-killing weapons only engage over extended time periods.

Finally, previous studies on NK cells’ immune surveillance of senescent cells have cultured them in very high levels of interleukin-2 (IL-2), an immune-signaling molecule that triggers NK cells to create more of themselves and makes them more aggressive. At SRF, Dr. Sharma used levels that reflect levels in the body.

The first set of discoveries revealed by this new system: even when the ratio between NK and their potential targets is quite low, introducing more NK cells into the mix tends to kill more senescent cells, but at the expense of killing more and more healthy bystander cells.

All around, the new paper sets up the SRF ApoptoSENS team — and other scientists who can now read the findings for themselves — on a better path to identify ways to rejuvenate or reinforce senescent cell immune surveillance, reinvigorating NK cells to make them battle-ready once again.

Reference

Kim K, Admasu TD, Stolzing A, Sharma A. Enhanced co-culture and enrichment of human natural killer cells for the selective clearance of senescent cells. Aging (Albany NY). 2022 Mar 4;14(5):2131-2147. doi: 10.18632/aging.203931. Epub 2022 Mar 4. PMID: 35245208; PMCID: PMC8954966.

New Peer-Reviewed Paper from SENS Research Foundation Researchers Reveals Tools to Harness Immune Cells to Seek and Destroy Senescent Cells

Senolytics — drugs that selectively destroy senescent cells (senolytics) — have been shown to powerfully rejuvenate mice and to reverse multiple diseases of aging in animals, from atherosclerosis, to kidney disease, to osteoporosis, to Parkinson’s disease — and beyond. But because these drugs target pathways that are necessary for normal cell function, they can come with side-effects — the most notable being the crash in platelets (and resulting risk of fatal bleeds or strokes) that can accompany the experimental senolytic navitoclax.

But our bodies are actually equipped with an inborn army of immune cells that selectively identify and destroy senescent cells. To date, the most important of these “immunosenolytic” soldiers have seemed to be Natural Killer cells (NK cells) — though we will have an announcement to make on this front in the coming months. But if the body already has this defensive force, how do senescent cells still manage to accumulate in our tissues with age and wreak havoc on our health?

SENS Research Foundation scientists are working to harness NK cells to more safely and effectively clear senescent cells out of our tissues. Dr. Amit Sharma and his team at SRF are developing ways to either rejuvenate our own NK cells’ ability to detect and destroy senescent cells in aging tissues, or to augment that capacity with NK cells engineered to be more lethal senescent cell hunters. To reach those goals, they realized they needed a more efficient way to create large numbers of NK cells from mixed white blood cells isolated from human blood. In new peer-reviewed scientific paper, they showed other scientists how they did it. Their main innovation might seem to be an obvious one: to actually isolate NK cells to study them. Previous scientists have mostly used very mixed populations of blood cells, sometimes removing T-cells or other specific cell types but never isolating NK cells exclusively. Dr. Sharma used an existing kit to make sure that what they were seeing came from the NK cells and not from other cell types.

They also saw that the way that previous researchers had studied NK cells’ ability to destroy senescent cells was quite different from the conditions NK cells actually confront as they patrol for NK cells in the body, potentially leading scientists to chase after interventions that work well in a Petri dish but have no effect or are unsafe when carried out in living, breathing humans. This is probably because most scientists conducting these studies don’t have a specialized background in immunology: instead, they design their experiments based on a general background in the biology of aging or cancer biology, or as specialists in senescence per se, but The biggest problem the SRF group corrected is that previous studies have cultured low numbers of senescent cells together with very high numbers of NK cells, creating a situation where NK cells are effectively shooting zombie fish in a barrel. The Sharma lab tested more realistic conditions in which one NK cell encounters one senescent cell, or no more than three, instead of ratios as high as one NK to 20 or even 80 senescent targets.

Conversely, having given NK cells so many senescent cell targets that they can hardly fail to kill some, most previous studies have only set NK cells loose for a few hours, when NK cells have a half-life in the body of ten hours. So the Sharma lab gave NK cells an amount of time to engage their enemies that reflects how long they actually hang out in tissues, with experiments running from 16 hours to four days. This also gives the NK cells the ability to reveal their full range of powers, since some of their cell-killing weapons only engage over extended time periods.

Finally, previous studies on NK cells’ immune surveillance of senescent cells have cultured them in very high levels of interleukin-2 (IL-2), an immune-signaling molecule that triggers NK cells to create more of themselves and makes them more aggressive. At SRF, Dr. Sharma used levels that reflect levels in the body. 

The first set of discoveries revealed by this new system: NK cells are actually most selective for senescent cells when the ratio between NK and their potential targets are quite low. As you introduce more and more targets into the mix, NK cells tend to kill more senescent cells, but also kill more and more healthy bystander cells. Additionally, their preliminary evidence suggests that NK cells from younger male subjects were more effective at killing senescent cells compared to female subjects, and also more effectively than older people of either gender. This is consistent with previous reports that older people’s NK cell armies included more dysfunctional or exhausted NK cells, which release less of the key immune signaling molecule interferon gamma (IFN-γ) and produce less of the chemicals needed to execute their targets. IF their initial finding of reduced senescent cell-killing ability pans out in a larger study, they can look at these and other mechanisms as potential reasons why and then look for ways to reverse or sidestep the effect of aging.

All around, the new paper sets up the SRF immunosenolytic team — and other scientists who can now read the findings for themselves — on a better path to identify ways to rejuvenate or reinforce senescent cell immune surveillance, reinvigorating NK cells to make them battle-ready once again.

Reference

Kim K, Admasu TD, Stolzing A, Sharma A. Enhanced co-culture and enrichment of human natural killer cells for the selective clearance of senescent cells. Aging (Albany NY). 2022 Mar 4;14(5):2131-2147. doi: 10.18632/aging.203931. Epub 2022 Mar 4. PMID: 35245208; PMCID: PMC8954966.

Michael Rae and Dr. Robert Rodgers discuss Parkinson’s and aging

Parkinson’s disease, like all the so-called diseases of aging, is what happens when the particular metabolic demands on specific cell and tissue types inflict enough damage on themselves to render them unable to do their jobs. As more and more of those cells and tissues become dysfunctional over time, the functional reserve of those tissues is slowly drained, until core function can no longer be sustained and the symptoms of that widespread cellular and molecular injury erupt.

In this interview with the Parkinson’s Recovery radio program, SENS Research Foundation’s science writer Michael Rae discusses “The coming rejuvenation biotechnology revolution for Parkinson’s disease.” In it, they discussed how the cellular and molecular damage of aging most closely involved in Parkinson’s can be removed, replaced, or repaired using rejuvenation biotechnologies, and research underway to make it happen. Here is some of what they talked about.

New Cells for Old …

The most prominent kind of aging damage driving Parkinson’s is the loss of specialized neurons producing the molecular messenger dopamine in a defined area of the brain. Signaling from these neurons suppresses the unregulated firing of neurons controlling motion in the brain, so as these neurons are lost to aging and additional insults, the ability to suppress this unwanted firing declines. Eventually, this becomes manifest as the “motor symptoms” of Parkinson’s: the tremors of the hands, shaking of the head, and problems with walking balance.

The rejuvenation biotechnology solution to this problem is repleniSENS: replacing the lost dopamine-producing neurons with fresh young ones. Early human clinical trials using cells derived from aborted fetuses had mixed results, but a small percentage of the patients who received the cells experienced such spectacular results scientists spent the next several decades working out the cell types, transplant sites, and other details to optimize the procedure so that all people suffering PD  (and eventually, all of us) could benefit.

In addition to what we learned through the ensuing decades of painstaking progress, we now have Shinya Yamanaka’s Nobel-prizewinning biotechnological breakthrough: the ability to take common differentiated cells (such as deep-layer skin cells) and reprogram them into  induced pluripotent stem cells (iPSC), which have the full developmental potential of embryonic stem cells and can be nudged to become any cell type we like — including dopamine-producing neurons for cell replacement.  Today, BlueRock Therapeutics, a stem cell company now owned by Bayer (yes, the aspirin people) is running a clinical trial grafting replacement neurons into the brains of patients with PD. Unlike others, BlueRock is not starting the process off with a patient’s own cells, but is using healthy donor cells from the general public, from which it then uses proprietary bioprocessing to create stable master cell banks of what they call “universal iPSCs” that they have found to be compatible with any patient. It is these cells that are then turned into dopaminergic neurons for transplant into the brain of PD patients — or, in the future, heart muscle cells for people with heart failure, and other medical use-cases.

Other groups are taking the patient-identical route. These include Dr. Jun Takahashi of Kyoto University in Japan, whose small ongoing trial recruited just 7 subjects and administered cells to its first patient in November of 2018, and Aspen Biotechnologies, which is led by Dr. Jeanne Loring at the Scripps Institute, a good friend of SENS Research Foundation. Additionally, it was only just revealed last year that a dramatic self-funded experiment by a wealthy PD sufferer resulted in millions of his own reprogrammed cells being transplanted into his brain as early as September 2017. And we’re even still learning things about grafting fetal neurons, because of a revamped European trial with curtailed ambitions known as Transeuro.

… And Out with the Old!

Meanwhile, we’ve learned about the evidence supporting a causal role for senescent cells in PD — and the potential of apoptoSENS (destruction of dysfunctional cells) to help keep these “zombie” cells from destroying some of those dopamine-producing neurons in the first place. People with PD have more senescent cells in their brains than do aging people not diagnosed with a specific neurological disease — specifically, senescent astrocytes, which help maintain the integrity of the crucial barrier that protects the brain from toxins in the circulation, and that also act as a kind of support cell for the neurons, providing them with nutrients and maintaining the balance of ionic flows. Scientists led by Julie Anderson and Judith Campisi at the Buck institute showed in animal models and cell culture that when astrocytes turn senescent, betray the very neurons they exist to protect and support, killing them.

But purging senescent astrocytes from the brains of mice with a model of PD prevented the loss of dopamine-producing neurons and enabling the generation of new neurons to begin again. This meant that after senolytic treatment, the PD mice were still able to move like non-PD mice. With ongoing trials of senolytic drugs and a host of startups in the space, the potential to bring this experiment to life in aging humans is breathtaking.

The Roto-Rooter Route to Rejuvenation

They also talked about the many lysoSENS immunotherapies in clinical trials or in the pipeline to remove aggregated alpha-synuclein from aging neurons and prevent the “nonmotor symptoms” of PD, and the related role of “minor” mutations in a lysosomal enzyme that create a vicious circle with alpha-synuclein — and Aspen Biotechnology’s plans to eliminate the problem.

And much more! Hear the full audio here.

Use of this Web site constitutes acceptance of the Terms of Use and Privacy Policy.

© 2022 SENS Research Foundation – ALL RIGHTS RESERVED

Thank you for Subscribing to the SENS Research Foundation Newsletter.

You can also

or

You can