A Letter to the Economist

To the Editors:

Your special report highlighted the growing number of people suffering dementia as one of the many terrible effects of an aging world. It did not consider the potential of medical intervention into aging itself to mitigate that future. Like all forms of age-related ill-health, dementia is caused by the accumulation of cellular and molecular damage in our tissues with age. We at SENS Research Foundation develop therapies to remove and repair this damage, so as to postpone (eventually indefinitely) age-related disease and debility, including neurodegenerative aging diseases such as Alzheimer’s disease (AD).

One such therapy is maintenance of the brain’s neurons. A key subpopulation of these cells is selectively lost in AD, and a strategy to replace these and other neurons lost to aging processes is essential to maintaining cognitive function.

Only recently have scientists established methods to reliably transplant neuronal precursor cells into the brain in ways that allow them to integrate into and function within existing synaptic networks. Unfortunately, the transplant procedures are laborious and invasive and cannot scale to reach all the affected areas of the brain.

We sponsor work in this area by Dr. Jean Hébert of Albert Einstein College of Medicine. Dr. Hébert has developed a new strategy to overcome this problem using microglia, a non-neuronal brain cell type capable of dispersing extensively throughout the brain upon implantation if a favorable space is made. By engineering microglia to transform into neurons upon administration of a drug, and using another drug strategy to create favorable space for them across the brain, Dr. Hébert proposes to deliver working neurons all across the aging brain, allowing the continuing replacement of neurons lost to AD, to trauma, and to other aging processes.

Jim O’Neill, CEO

Mask Competition

The SRF Design-a-Mask Competition!

Mask Up With SRF

Throughout the COVID-19 pandemic, SENS Research Foundation’s team at our Research Center in Mountain View have continued to work as intensively as local regulations permit. Of course, that includes the mandatory use of face coverings.

We invited all our supporters to submit designs for an official SRF mask. As well as being worn by our staff, these masks will be available in limited supply to anyone who’d like to  support our work to end age-related disease and disability.

At the close of the competition, we’ll select the best three entries and run a poll on SRF’s Facebook Page to allow our supporters to vote for their favourite design.

The Importance of Masks

It’s widely agreed that wearing a mask reduces your chances of transmitting SARS-CoV-2 to others, even during the critical period of “silent spread,” when you have no symptoms and are most likely to transmit the virus to your friends and neighbors.

There’s now a growing body of evidence that wearing a mask also protects you from becoming infected, as well as evidence (reviewed in a recent article from the New England Journal of Medicine) that individuals who are infected despite wearing a mask are still several times less likely to develop severe illness. This may be because face coverings significantly reduce the initial dose of the virus received, giving the body more time to mount a response before things get out of hand.

Competition Rules

  1. The competition has now ended. Please see below for pre-ordering an SRF mask.
  2. All entries must comply with the following specifications:
    • Entries must be final designs and printable.
    • Use the design template to ensure proper sizing.
    • Vector graphics are strongly preferred.
    • Any raster graphics must be 300 dpi or higher.
    • Files should be in PDF, TIFF, PSD, IDML, EPS, or AI format.
    • Files should be submitted HERE.
  3. The design submitted must be relevant to SENS and/or rejuvenation biotechnology.
  4. All submitted work must be the original work of the entrant(s) and must not include, be based on, or derived from any pre-existing or third-party designs, trademarks, or copyrighted images.
  5. All entries will become the property of SENS Foundation, Inc. By submitting an entry, each entrant agrees that any and all intellectual property rights in the logo design are deemed assigned to SENS Foundation, Inc.
  6. Selection criteria:
    1. Relevance.
    2. Originality.

For questions, please contact [email protected].

Mask Availability

Our masks will be produced shortly after the selection of the winning design, and will be available through the end of 2020 – while supplies last.

If you’d like to secure an official SRF mask for yourself, you can pre-order by making a donation through the PayPal links below at any time before the final winner is announced.

Revel Strengthens Boards

SRF spin-off Revel Pharmaceuticals, a privately held biotechnology company creating therapeutics to reverse and repair damage that results from aging – particularly extracellular crosslinks – has announced recent additions to its Board of Directors and Scientific Advisory Board.

Joining as a member of the Board of Directors is Jennifer Cochran, Ph.D. and joining as a member of the Scientific Advisory Board is Vincent Monnier, Ph.D. “We are thrilled to attract stellar leadership that matches the level of promise of Revel’s mission of attacking diseases of aging,” said Aaron Cravens, Revel co-founder and CEO.

For more information, read the full announcement on Revel’s site.

Defatting the Streaks

Image from "Affinity-Driven Design of Cargo-Switching Nanoparticles to Leverage a Cholesterol-Rich Microenvironment for Atherosclerosis Therapy"

The removal of damaged material from within atherosclerotic plaques (“fatty streaks”) to restore cardiovascular health is a key component of SENS, now being developed for the clinic by SRF ally Underdog Pharmaceuticals. Exciting new preclinical results from another group using this strategy have recently been published in ACS Nano.

Act Now to Help Us Buy Time… In Time!

A message from Herbie Hancock

Act Now to Help Us Buy Time... In Time!

If you’ve put charitable money into a donor-advised fund (DAF), you know that a key advantage of these funds is that they let you put charitable money aside when you have a jump in earnings, and watch for the best time and project to invest your money. We’re here to tell you that now is that time!

#HalfMyDAF is an initiative of tech executives (and DAF holders) David and Jennifer Risher, who noticed that a lot of DAF money had been sitting idle for many years, and set out to use their DAF accounts to motivate other DAF donors to put their escrowed monies to work immediately, in these challenging times.

#HalfMyDAF is a matching-grant competition: DAF holders make a donation to the cause they value most, register their donation with the website, and thereby buy a “ticket” for the competition.* Then, over the course of the competition, about 300 registered DAF donors will be randomly selected to have their donation doubled via a #HalfMyDAF matching grant of up to $25,000!

We want SENS Research Foundation to be your #HalfMyDAF cause. And now is an especially good time for this competition to fall. Pandemic or no pandemic, degenerative aging relentlessly damages our bodies and those of our loved ones. But the terrible and selective toll of COVID-19 on older people has put the crippling effects of the aging process into stark relief, even for many who normally avoid thinking about aging or dreaming that something could be done about it.

COVID-19 mercilessly targets the vulnerabilities of the aging body. The disease exploits the waning power of the immune system to keep the virus from establishing a foothold and eliminate the infection if it starts. It continues on to ravage the aging body’s structural weaknesses (so-called “comorbidities”), lack of resilience, and loss of metabolic flexibility. Rejuvenating the body can not only thwart the chronic diseases that are driven by degenerative aging – it is the ultimate defense against future plagues as well.

So evidence to date suggests that rejuvenation biotechnologies targeting senescent cells can both protect the body against SARS-CoV-2 infection, and restore the youthful resilience of the body’s organs and tissues against COVID-19 if the virus takes hold. While most research to date has focused on senolytic drugs, our team at SENS Research Foundation are now working to restore and augment the aging immune system’s ability to eliminate senescent cells more physiologically. Natural killer cells (NK cells) are the main cell type involved in recognizing and extirpating senescent cells from our bodies. Dr. Amit Sharma and Elena Fulton have collected preliminary data at our Research Center showing that the proportion of NK cells that exhibit markers of strong cell-killing ability declines sharply with age. To confirm this preliminary finding, they will look for an age-related reduction in NK cells’ ability to kill senescent cells, using NK cells freshly isolated from young adult, middle-aged, and older people. They will run parallel tests on NK cells from the spleens of young (6 months) and old (24 months) mice.

Schematic: the age-dependent accumulation of senescent cells is in part due to impaired clearance of senescent cells by NK cells with age. Evidence suggests two factors are involved.

First, the fraction of NK cells with highly potent cell-killing function declines with age. Second, over time senescent cells lose the ligands that activate NK cells’ killing function, and begin to express ligands that signal to the NK cells that they are normal cells and should be left alone.

Developing interventions that target these two problems will allow us to enhance and rejuvenate our intrinsic senescent cell-killing ability, mitigating aging and age-associated diseases.

Moving from basic research to anti-aging intervention, the team is developing strategies to enhance senescent-cell-killing ability in old NK cells. They will test rejuvenation strategies including adoptive transfer of young human and mouse NK cells into aging mice, and agents that strip away the protective shielding that senescent cells throw up to defend themselves against NK cells. If transferring young NK cells works as a proof of concept, the team will move forward by adapting CAR-NK cell technology — a cutting-edge immune transfer biotechnology that is currently promising to revolutionize immunotherapy for some cancers at MD Anderson and elsewhere — to instead selectively target senescent cells.

By restoring and augmenting the body’s youthful ability to purge itself of dysfunctional senescent cells, these cells can be targeted without incurring the side-effects of destroying senescent cells when they’re playing their useful physiological roles in wound healing and regeneration, or the other potential toxicities of senolytic drugs (such as dangerous hits on platelets with Navitoclax).

So there is a double incentive to open up the funds locked up in your DAF today: the potential to double your donation via the #HalfMyDAF challenge, and the urgent object lesson of a global pandemic, which shows the potential of our research to make a difference against this or future plagues that will seek us out mercilessly if we continue to age as usual.

We urge you to visit #HalfMyDAF today and make your pledge in support of SENS Research Foundation and the future of rejuvenation biotechnology. Don’t have a DAF, or have only just recently set one up? This project still needs your support and you can donate to us HERE!

 * To be eligible, you need to provide #HalfMyDAF with DAF confirmations showing that you’ve invested at least half of your DAF in new donations made between May 5th and September 30th. No, you can’t buy extra “tickets” by dividing your donation to the Foundation into multiple tranches: #HalfMyDAF will consolidate all donations you make to a given cause and treat it as a single grant. The best way to maximize the odds that SENS Research Foundation receives a match is to encourage other DAF holders to join you in buying “tickets” of their own, both directly (by reaching out to DAF holders you know), and also by announcing your donation on social media with the #HalfMyDAF hashtag).

Which Links Must Be Broken?

The collagen strands that provide strength and flexibility to our tissues are crosslinked by chemical bonds that tie the component proteins into a mesh-like structure. Until recently, the consensus in the field has been that a gradual increase in such crosslinks – and particularly those considered ‘irreversible’ due to their high stability – is a principle driver of the age-related loss of elasticity that leads ultimately to mechanical failure of the blood vessels, muscles, and other tissues.

The SENS platform proposes to resolve this class of damage by introducing enzymes or small molecule drugs capable of selectively degrading the offending crosslinks. However, the sheer number of crosslinks of a given kind may not be a good measure of how high a priority it ought to be for rejuvenation biotechnology: some crosslinks may have a disproportionate effect on tissue elasticity depending on where they occur in the protein strand, how tightly they bind, and how much they interfere with the body’s ability break down and renew the tissue.

Our funded project in the laboratory of Dr. Jonathan Clark at Cambridge’s Babraham Institute is focused on precisely this question of prioritization. Three new papers released by the group this year have established that the simple model in which highly stable crosslinks accumulate over the lifespan is unlikely to be the full story; provided the first evidence that crosslinking within collagen can vary in response to mechanical forces; and identified a potential relationship between specific crosslink precursors and the cancer microenvironment. These results will be crucial to the development of effective therapeutics.

Therapy to Destroy Cells with Reactivated “Jumping Genes”

Roswell Park Comprehensive Cancer Center

Principal Investigator: Andrei Gudkov
Research Team: Marina Antoch, Amy Stablewski, Nick Neznanov, Lilya Novototskaya, Olga Leontieva

Nearly half of the mammalian genome is long and short interspersed virus-like repetitive elements (LINEs and SINEs), which spread through the process of retrotransposition. Numerous intracellular mechanisms exist to silence these elements, but unfortunately these mechanisms decline with age. Active copies of these elements thus cause DNA damage over time as they integrate into genes and disrupt their functions. Cells with many such dysfunctions can mimic viral infections and trigger the production of the pro-inflammatory substance interferon (IFN). Normally, such cells are removed by the immune system, but as the immune system itself ages, it becomes less effective at this type of cleanup. This leads to “inflamm-aging”, which damages tissues further.

Analysis of blind mole rats, which exhibit both a natural IFN-driven mechanism for eradicating cells with damaged DNA as well as exceptionally long lifespans, has yielded observations supporting the LINE/SINE hypothesis.

SRF is sponsoring a study to test the impact of the removal of damaged cells on healthspan and lifespan, via the creation of a special transgenic mouse at the Roswell Park Comprehensive Cancer Center.

Research Highlights:

This project began in the last quarter of 2019, and the Roswell Park team is now generating the transgenic mouse model. The group has already verified the transgene expression and activity in a cell culture model. Newborn mice are currently being screened for successful integration of the gene construct designed by the team. The final mouse model will allow the team to track the amount of IFN positive cells, and a lifespan study will begin later this year.

COVID-19 and Aging

A message from Edward James Olmos

Why is COVID-19 so deadly to the elderly?

A pandemic has swept the globe, leaving more than two million dead. In response, many wait in isolation, while health workers face the disease head-on in our hospitals, fighting to save patients from “drowning on dry land.”

Through all the updates on the sick and the dead, on testing and public health guidance, there remains one constant: by far the greatest predictor of death from this plague is age. The so-called comorbidities predisposing patients to death from COVID-19 — chronic lung diseases, damaged kidneys and hearts, high blood pressure, diabetes — are themselves aspects of aging, erupting in their distinctive ways in particular tissues. Flattening this “demographic curve” of degenerative aging would reduce COVID-19 to a disease similar in impact to an average recent flu season (and make future flu seasons less deadly), while also putting an end to the staggering toll of age-related death and debility that ticks on in the background even now, day in and day out, pandemic or none.

Ending that toll is our mission. At SENS Research Foundation (SRF), we develop rejuvenation biotechnologies: new therapies that will repair the accumulated cellular and molecular damage in our tissues and restore youthful function.

The SARS-CoV-2 pandemic is both an immediate, pressing danger, and a call to action. It demonstrates the critical need for better long-term strategies for addressing threats to human life. As members of the global scientific community, all of us at SRF acknowledge the need to adapt and apply our expertise and experience to the current crisis. (SARS-CoV-2 is the coronavirus that causes the disease called SARS-2 or COVID-19.)

Below, we outline some of the ways in which specific forms of aging damage are relevant to diseases like COVID-19 – and how some of our research programs may help render this and other viruses far less dangerous in the future.

Aging’s effect on COVID-19 mortality rate, and the anticipated effects of future rejuvenation biotechnologies.

Data taken from Lancet Infect Dis 2020 Mar 30. pii: S1473-3099(20)30243-7

Comorbidity by age group.

 Image credit: Lancet 380(9836):37-43.

Ending that toll is our mission. At SENS Research Foundation (SRF), we develop rejuvenation biotechnologies: new therapies that will repair the accumulated cellular and molecular damage in our tissues and restore youthful function.

The SARS-CoV-2 pandemic is both an immediate, pressing danger, and a call to action. It demonstrates the critical need for better long-term strategies for addressing threats to human life. As members of the global scientific community, all of us at SRF acknowledge the need to adapt and apply our expertise and experience to the current crisis. (SARS-CoV-2 is the coronavirus that causes the disease called SARS-2 or COVID-19.)

Below, we outline some of the ways in which specific forms of aging damage are relevant to diseases like COVID-19 – and how some of our research programs may help render this and other viruses far less dangerous in the future.

Rejuvenate the Immune System

Strong and early T-cell responses appear to be critical to the immune system’s ability to successfully fight off SARS-CoV2. CD8+ (“killer”) T-cells, and other parts of the immune system fight viruses by eliminating cells that are infected with the virus, preventing them from becoming factories to churn out more infectious particles. But recent studies showed impaired cytotoxic T-cell function in older COVID-19 patients might be causally linked to severity of the infection (PMID: 32948688, 32463803). Older people mount a much weaker and less complete immune response to both infections and to vaccines, even as they suffer increasingly from overactive parts of the immune response, including autoimmunity and chronic inflammation.

Two key parts of this immunosenescence (aging of the immune system) are waning production of naïve T-cells by the aging thymus and damage to the lymph nodes, such that the lymph nodes are no longer able to keep emerging T-cells alive, functional, and ready for future threats. SENS Research Foundation has sponsored several projects aimed at developing damage-repair technologies to restore aging T-cell numbers and function, including pilot studies of a T-cell scrubber that might clear out a specific class of dysfunctional T-cells and early-stage work toward a tissue-engineered thymus, along with a pilot animal study to simulate the effects of both interventions.

In today’s pandemic, COVID-19 patients suffer from an exhaustion of both CD8+ (“killer”) T-cells as well as of natural killer (NK) cells. Whereas T-cells and B-cells are specialists, focused on eliminating specifically-identified threats (such as cells infected with specific viruses), NK cells are sentinels patrolling the perimeter of a military camp, on the lookout for anything that looks like it doesn’t belong. NK cells attack abnormal cell types such as cancer cells, cells infected by viruses like SARS-CoV-2, and senescent cells — that is, cells that have undergone changes that prevent them from replicating, and that spew out a witches’ brew of inflammatory signaling molecules, growth factors, and enzymes that break down proteins. This brew is called the senescence-associated secretory phenotype, or SASP.

Long before the pandemic hit, we knew that NK cells lose much of their effectiveness with age, meaning that aging people already come into the fight against infections like SARS-CoV-2 with these critical early responders weakened. At our Research Center, Dr. Amit Sharma and Elena Fulton have been developing strategies to rejuvenate and reinforce NK cells in aging people. They recently collected preliminary data showing that the proportion of NK cells exhibiting markers of strong cell-killing ability declines sharply with age. To confirm this preliminary finding, they will look for an age-related reduction in NK cells’ ability to kill senescent cells, using NK cells freshly isolated from young adult, middle-aged, and older people. They will run parallel tests on NK cells from the spleens of young (6 months) and old (24 months) mice. Moving from basic research to anti-aging intervention, the team is developing strategies to enhance senescent-cell-killing ability in old NK cells. They will test rejuvenation strategies including adoptive transfer of young NK cells into aging mice, and agents that sidestep the protective shielding that senescent cells throw up to defend themselves against NK cells.

If transferring young NK cells works as a proof of concept, it would support moving forward by adapting immune transfer biotechnologies already in use for cancer therapies to instead selectively target senescent cells. In CAR-T cell therapy for some cancers, a patient’s T-cells are drawn out with the blood, expanded in number, and engineered to express artificial CAR receptors. These receptors specifically target proteins found on the surface of the cancer cells, and the T-cells can also still attack cancer cells that are no longer displaying markers that T-cells normally need to identify and attack. These CAR-T cells are then re-infused into the patient to attack the cancer aggressively.

Recently, CAR-T cells were engineered to target senescent cells, zeroing in on a receptor that scientists tentatively identified as commonly displayed by them. At the same time, CAR engineering of cancer patient cells has been used with NK cells. This CAR-NK cell technology is very new, but has already revolutionized immunotherapy for some cancers at MD Anderson and elsewhere, and thirteen clinical trials are underway in other cancers, including some against which CAR-T therapy has not (or has not yet) proven effective.  And NK cells — not T-cells — are the natural immunological enemies of senescent cells. So by combining NK cells’ intrinsic senescent cell-stalking abilities with CAR receptors laser-focused on markers displayed on the senescent cell surface, the SRF team expects to generate a remarkable chimeric predator specialized in eliminating these cells.

Purge Senescent Cells

For Younger Lungs...

Some of the rejuvenation strategies being tested by Elena and Dr. Sharma will likely enhance aging NK cells’ ability to eliminate any kind of abnormal cell, including those infected by SARS-CoV-2. But the SENS lab is focused on rejuvenating the capacity of NK cells to eliminate senescent cells because of their broad role in driving aging pathology, and it’s not a coincidence that many of their ill effects directly impact a person’s vulnerability to COVID-19.

First is senescent cells’ role in driving fibrosis in our tissues. Multiple aspects of lung function decline with age, while fibrosis increases. Accordingly, diseases of the lung — including chronic obstructive pulmonary disease, lung cancer, and most especially idiopathic pulmonary fibrosis (IPF) — are profoundly age-related. Preliminary evidence suggests that the lung is one of the organs most burdened with senescent cells in aging in humans — a burden further exacerbated by IPF.

We’ve known for a while that the age-related loss of lung function is a massive driver of risk of death from pneumonia. Aging people not only have fewer functional alveoli available, but progressively lose the ability to inhale and exhale deeply to compensate for alveoli taken offline by the infection. Continuing research suggests that eliminating senescent cells in the lung may preserve and restore youthful lung function, leaving the lungs better prepared to endure the attack of the SARS-CoV-2 virus and other causes of pneumonia.

Senolytic drugs, which selectively kill senescent cells, have been shown to reverse lung fibrosis and other tissue fibrosis in aging mice. Studies in aging mice with inbuilt “suicide genes” demonstrate that ablating senescent cells in aging mice restores youthful lung compliance, suggesting an opportunity to do the same with other senescent-cell elimination strategies, such as restoring the ability of NK cells to eliminate them from tissues. Further supporting this, lung fibrosis is partially reversed by two different senolytic drugs in mouse models of IPF, and a third senolytic partially reversed lung fibrosis in mice whose lungs have suffered radiation damage.

... and a Rejuvenated Signaling Environment...

In addition to lung damage, another way that senescent cells may exacerbate COVID-19 involves the SASP cocktail of inflammatory factors and proteins that degrade the network of proteins that support the organs in which they’re embedded. Some researchers have argued that inflammatory factors in the SASP may also suppress the immune response to the virus underlying COVID-19 (SARS-CoV-2). This hypothesis is based on a number of previous studies showing that chronic inflammation caused by numerous different conditions interferes with the immune response to multiple other viruses, including blunting the immune system’s response to vaccines against influenza, yellow fever, and hepatitis B. Moreover, inflammation driven by macrophages in the lesions of patients with atherosclerosis suppress the activation of T-cells, and this is associated with the failure of T-cells from these patients to mount an effective T-cell response against the virus that causes chickenpox in children and shingles (herpes zoster) in older adults. In one study, damping down the release of inflammatory factors in the skin before administering a shingles vaccine virus boosted the T-cell response to the vaccine.

Inflammation is complicated, however: acute inflammatory responses to injury or infection are essential to wound repair and successful immune response, respectively, whereas the chronic inflammation of aging impairs both, drowning out the local ramp-up when immune cells are actually needed and instead dispersing those cells all over the body to sites riddled with aging damage, futilely trying to repair microscopic injuries they cannot resolve. This is why drugs and antibody therapies that simply force down the inflammatory response lead to vulnerability to infection.

The solution here is not to attack the inflammation, but to remove and repair the underlying damage of aging, thereby eliminating the source of chronic inflammatory stimulus while freeing up the rejuvenated tissues’ ability to mount an effective inflammatory response to acute threats.

A surprising example of this has emerged in the context of aging and COVID-19. As a result of the pandemic, people worldwide have become familiar with the “cytokine storm” — a severe inflammatory response that leads to immune derangement and the deadly acute respiratory distress syndrome (ARDS) that directly kills so many COVID patients. Cytokine storms are also involved in many other viral fatalities, and the fact that young people can mount aggressive cytokine storms is thought by many scientists to be the reason why so many middle-aged people were killed by the 1918 influenza epidemic, which normally stalks the elderly and extremely young infants and children while leaving middle-aged people alone.

But there’s a wrinkle on cytokine storms and aging in COVID-19. Chinese researchers have found that a delayed immune response to the virus, as much as the strength of it, predicts death from COVID-19, accompanied by higher levels of inflammatory factors at death and depleted levels of multiple immune cell types. A study in aging monkeys suggests reasons why. The researchers found young monkeys infected with SARS-CoV-2 quickly mounted a savage immune response, complete with extensive attack of macrophages and T-cells and high levels of inflammatory factors within the first week of infection, but were quickly able to recover after that. By contrast, the immune response was delayed in old monkeys — and this seemed to have cost them. Having gotten started late, the old animals’ immune systems seem to have attempted to make up for lost time, mounting a more severe cytokine storm that recruited even higher levels of infiltrating macrophages and drove a more persistent T-cell attack. Yet those aged T-cells were also less effective at actually fighting the virus, making the inflammation and immune cell attack on the tissues purely self-destructive — a story we have seen play too often in our hospitals.

One important component of the SASP is an inflammatory factor called IL-6, which rises with age and predicts the risk of frailty and death even without SARS-CoV-2 infection. A report suggests that a hospitalized COVID-19 patient’s IL-6 level is a strong risk factor for eventually requiring a ventilator, suggesting that senescent cells make aging people more vulnerable to the disease, and that senescent cell ablation could shore up this vulnerability. These findings are so compelling that some clinical centers treating critically ill COVID-19 patients are making experimental use of monoclonal antibody therapies such as tocilizumab and sarilumab, which block IL-6’s access to its receptors. But if we restore NK cells’ ability to eliminate senescent cells, people infected with SARS-CoV-2 would start off with lower IL-6 levels more characteristic of a young person, and thus better prepared for the fight.

In addition to IL-6, it’s recently been discovered that there is a network of factors emitted in the SASP that trigger the formation of blood clots and impede the countervailing factors that dissolve them. It’s long been known that an imbalance in these factors becomes increasingly common as people age, especially if they have risk factors for cardiovascular disease. The discovery that the SASP could tip the balance toward excessive coagulability, combined with the fact that aging people’s tissues become increasingly riddled with senescent cells over time, suggests that senescent cells and their SASP may be a key driver of this process.

Senescent cells’ possible culpability in the pro-clotting bias in aging people’s blood was already an important avenue for research before the rise of COVID-19, since the excessive tendency to form and maintain clots puts them at greater risk of heart attack, stroke, and venous thromboembolism (VTE) — abnormal clots forming in the veins. But it becomes a matter of acute focus in the face of multiple reports that high levels of markers of excessive clotting are common in COVID-19 patients at hospitalization, and foreshadow admission to the ICU and death from or with COVID-19 (in Holland and in Wuhan). Indeed, despite receiving prophylactic anti-clotting medication, nearly a third of Dutch patients with COVID-19 suffered from dangerous blood clots, including very commonly VTE that work their way up to cut off the lung tissue’s own blood supply, starving the lung itself of oxygen even as it is under attack by the virus and the patient’s own immune system.

Medical researchers have suggested a number of possible causes of excessive clotting specific to COVID-19, but as usual, the role of aging itself has been almost entirely ignored, despite the powerful influence of age in one’s risk of dying of the disease. Older people’s burden of senescent cells, the recent research suggests, may be predisposing them to a clotting crisis if infected by SARS-CoV-2.

Fortunately, the same research that originally identified the pro-clotting cocktail in the SASP also suggests that rejuvenation biotechnology could eliminate the associated risk of dangerous blood clots. Mice, like people, suffer a rise in senescent cell burden when given the chemotherapy drug doxorubicin, and the cells release SASP factors that favor the formation and stability of blood clots. In response, the mice produce higher levels of clot-initiating platelets, and those platelets are placed on a hair trigger. Activating a senescent-cell-destroying suicide gene prevented all of these things from happening, suggesting that purging aging cells from aging people could also leave them better prepared to survive an infection with SARS-CoV-2. Conversely, researchers at the Mayo Clinic have discovered that proteins from the SARS-CoV-2 virus exacerbate the SASP in human senescent cells, creating a vicious cycle of inflammation consistent with the ravages of the virus in older people.

... and Now in Human Trials

Work is already underway to translate these exciting results into human rejuvenation therapies. Mayo Clinic researchers last year conducted a very early-stage clinical trial of drugs that trigger self-destruction of senescent cells in human patients with IPF. Although there were few clearly apparent benefits to senolytic therapy in this study, it was too short-term and involved too few patients (just 14) to expect anything obvious: happily, the researchers are working to expand this pilot study into a larger clinical trial, and other such trials are underway in patients with kidney disease and osteoarthritis, diseases also driven by senescent cells. We will soon begin seeing what these therapies can do to maintain our health and resilience against the forces of degenerative aging and COVID-19.

In fact, there’s now proof-of-concept evidence that eliminating senescent cells can protect the body against mouse beta-coronavirus — the same subgroup of coronaviruses to which SARS-CoV-2 belongs.  Mayo Clinic scientists recently found that administering a senolytic agent allows mice to survive infection with mouse beta-coronavirus. The evidence is so compelling — and the intensity of the pandemic so threatening — that the FDA has green-lit them to initiate a clinical trial of a senolytic for older people hospitalized with COVID-19, aiming to keep them from drowning in the abnormal age-related cytokine storm.

Trigger Self-Destruction of Mutation-Prone Cells

More than half of the human genome is invasive genetic data left behind by viruses, including millions of retrotransposons. Retrotransposons are “dead” DNA, but their long- and short- interspersed virus-like repetitive elements (LINEs and SINEs) encode machinery that —under certain circumstances — allows them to reactivate, replicate, and spread through the genome. These reactivation events can cause mutations in our functional genes and even disrupt the normal expression of non-mutated genes, leading to cancer, cellular self-destruction (apoptosis), and cellular senescence.

To develop a proof of concept for a new class of “retrolytic” drugs that would ablate these cells before they can further damage the body, SENS Research Foundation is sponsoring work by Dr. Andrei Gudkov and his team at the Roswell Park Comprehensive Cancer Center for a suicide-gene system similar to the groundbreaking INK-ATTAC system that paved the way for the senolytic revolution. As a side-benefit, the gene whose expression will activate the retrolytic suicide gene is also activated in cells with active viral infection (such as SARS-CoV-2), which may eliminate such cells before they are hijacked by the virus to replicate itself.

Transplant Mitochondria to Rescue Critical Lung Cells

Recent gene-expression and protein distribution studies demonstrate that the ACE2 receptor — the critical loophole through which the SARS-CoV-2 virus slips into our cells — is more enriched in a type of lung cell known as AT2 cells, and COVID-19 patient autopsy reports indicate that these cells are subject to a terrible assault during the disease. AT2 cells are critical support cells for type I alveoli — the tiny air sacs that expand and contract to effect gas exchange and respiration. AT2 cells produce the pulmonary surfactant that allows type I alveoli to expand again after contraction by reducing alveolar surface tension. This surfactant also facilitates the exchange of gases between the oxygen-poor, CO2-enriched venous blood and the relatively oxygen-rich air in the lungs; we believe the virus’s assault on these cells is a major contributor to respiratory failure.

It’s these same AT2 cells that fail in an animal model of septic pneumonia, and these mice are rescued by transplanting bone marrow stem cells that donate their mitochondria to the failing AT2. Dr. Amutha Boominathan, Nana Anti, and Lauren Kirk of our mitochondrial mutation rescue team have been developing our mitochondrial transplantation protocol. Their initial target is different, but we hope it will treat many conditions of acute energy depletion, as is already being done in small open clinical trials for babies with heart damage from ischemia-reperfusion injury.

A New Generation of SENS Scientists in a New Model System

Over the summer, SRF partnered with Dr. Evan Snyder at the Sanford Consortium for Regenerative Medicine to learn more about COVID-19. Under the expert mentorship of the Snyder lab, six SRF Summer Scholars successfully established innovative lung and brain organoid models as well as a lung epithelium model to uncover how SARS-CoV-2 infects these organs, investigate drugs that might treat or ameliorate the disease, and look for clues about what makes aging people more vulnerable. These models contain blood vessels, since abnormal clotting and damage to blood vessels are critical vulnerabilities in COVID-19. The lung epithelial model also offers the potential to identify age-related or virus-induced damage to specialized lung cells’ ability to produce the critical surfactant needed to keep lung air sacs functional. Our Scholars demonstrated that these systems could be infected with the virus and that they could use them to test drugs that might thwart that infection and to profile aspects of COVID-19 that might make the elderly so vulnerable (including increased inflammation, compromised vasculature, loss of critical lung proteins, and aging brain cells). These studies establish systems that may accelerate progress toward novel therapies against COVID-19 and against lung and brain aging.


Like the pandemic, aging touches all of us. It creeps silently through our tissues, progressively crippling our minds and bodies, and eventually killing us if we don’t die first of accident, violence, or other abrupt age-independent causes. In COVID-19, the damage caused by aging is the largest factor in determining who lives and who dies, even if the trigger was pulled by a virus spread by globalization. The need for rejuvenation biotechnologies as part of medicine has never been clearer, and so we strengthen our resolve. Restoring our cells and tissues to youthful vigor will allow us to step out of our ancient lockdown and into a bright future.

Watch the space below for announcements and progress.

Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy.
Onder G, Rezza G, Brusaferro S.
JAMA. 2020 Mar 23. doi: 10.1001/jama.2020.4683. [Epub ahead of print] PubMed PMID: 32203977.

The dramatically higher case-fatality rate for COVID-19 in Italy as compared with anywhere else in the world (including in the epicenter of the pandemic in Wuhan, China) has been the subject of much speculation and concern. These investigators find the phenomenon to be almost entirely explained via the age structures of the populations, with a much larger share of persons aged >65 in Italy. Looking within each age group, the case-fatality rates in Italy and China are highly comparable for all persons >65, but were higher in Italy in persons age >70 and even more so in those >80 years; these numbers are skewed, however, by the particularly low number of people in these age groups in China as a share of persons >65, and especially the lack of any patients aged >90 in the Chinese reports, who were at very greatly increased risk of death in Italy.

Convalescent plasma transfusion for the treatment of COVID-19: Systematic review.
Rajendran K, Narayanasamy K, Rangarajan J, Rathinam J, Natarajan M, Ramachandran A.
J Med Virol. 2020 May 1. doi: 10.1002/jmv.25961. [Epub ahead of print] Review. PubMed PMID: 32356910.

Convalescent plasma is a very old therapy, first used for diphtheria in the late nineteenth century. Doctors often turn to it for new infections in the absence of established medical therapy, and this has been the case in COVID-19. Available studies appear generally favorable, but are all very small and have no control group, and the evidence for convalescent plasma in most diseases is weak; it was used successfully to treat Ebola, but in a randomized trial of 140 children and adults, it was found no more effective against influenza than control plasma from uninfected subjects. Importantly, it did seem to have salutary effects in the original SARS virus, including some controlled trials; however, none of the trials were of high quality. Three randomized controlled trials are underway in the United States to test the intervention: one to protect medical workers who are not yet infected from the disease, and two in hospitalized patients at different stages in the disease progression.

 A key limitation of the therapy is the low ratio of recovered patients compared to those needing therapy; if it works, it could be the basis for a monoclonal antibody therapy, which could be scaled up to treat far more patients and could likely be made more effective. It would also provide some preliminary confidence for the possibility of a vaccine, whose prospects are uncertain at this time. Fortunately there has been no evidence of antibody-dependent enhancement (ADE) in the use of convalescent plasma for either SARS or COVID-19, although ADE was observed in animal models of SARS and in response to an experimental SARS vaccine in nonhuman primates.

New 2020 Publications

2020 has already seen six new SRF-supported papers – including validation of a key tactic to prevent mitochondrial aging by our MitoSENS team, and an in-depth review coauthored by SRF, Underdog Pharmaceuticals and professor W. Gray Jerome on the major LysoSENS target 7-ketocholesterol.

Read the MitoSENS and LysoSENS papers for free at PubMed Central:

… or visit our Publications Library to see more of our recent work!

Revel Pharmaceuticals Launched

Glucosepane crosslink breaker research graduates from top Yale lab into the biotech world

Kizoo Technology Capital leads seed round financing at Revel Pharmaceuticals

SAN FRANCISCO/NEW HAVEN/BERLIN, Jan. 21, 2020 — For the past 10 years, Yale Professors David Spiegel and Jason Crawford have been working on tools to enable the development of glucosepane-cleaving drugs. Kizoo Technology Capital investors say now is the time to advance this groundbreaking research toward the clinic and are leading funding of a new company, Revel Pharmaceuticals Inc., founded by Drs. David Spiegel, Jason Crawford, and Aaron Cravens.

Kizoo leads the seed financing round at Revel, with Oculus co-founder Michael Antonov participating. SENS Research Foundation provided funding to the YaleGlycoSENS group for several years.

Glucosepane Biology in relation to Aging and Disease

The long-lived collagen proteins that give structure to our arteries, skin, and other tissues are continuously exposed to blood sugar and other highly reactive molecules necessary for life. Occasionally, these sugar molecules will bind to collagen and form toxic crosslinks that alter the physical properties of tissues and cause inflammation. As a result, tissues slowly stiffen with aging, leading to rising systolic blood pressure, skin aging, kidney damage, and increased risk of stroke and other damage to the brain.

Perhaps the most important of these Advanced Glycation End-products (AGE) crosslinks is a molecule called glucosepane. Revel is developing therapeutics that can cleave glucosepane crosslinks thus maintaining and restoring the elasticity of blood vessels, skin, and other tissues, and preventing the terrible effects of their age-related stiffening.

Revel opens a new category in the SENS repair approach to aging

The Yale group’s first major milestone – the first complete synthesis of glucosepane – was highly recognized when published in Science. Since then progress has been rapid, with development of glucosepane binding antibodies and discovery of therapeutic enzyme candidates capable of breaking up glucosepane crosslinks. Revel will build upon this progress by advancing the first GlycoSENS therapeutics into the clinic.

This is truly a first. We are proud to help Revel open an entirely new category in repairing a significant damage of aging – crosslinking of collagen. Glucosepane crosslinks may cause not only wrinkles on your face but also lead to age-related rising blood pressure and possibly stroke.” says Frank Schueler, Managing Director of Kizoo Technology Capital.

David Spiegel, MD, PhD, Professor of Chemistry at Yale University and Revel founder says: “We are delighted to join Kizoo in building a world-class team to advance crosslink-breaking therapeutics into the clinic. These first-in-class agents have enormous potential to help patients suffering from a wide range of diseases.

Collagen is the infrastructure of our bodies – in every tissue, supporting cellular function and health – but with aging, this critical molecular infrastructure accumulates damage. By clearing out this damage, we can restore tissue function and repair the body. Revel is one of only a few companies taking a repair-centric approach to treat diseases of aging and one day our AGE-cleaving therapeutics will undo this damage at the molecular level.” says Aaron Cravens, co-Founder of Revel Pharmaceuticals.

About Revel

Revel Pharmaceuticals is a biotechnology company located in San Francisco, CA. with a technology platform based on the work of Yale Professors David Spiegel and Jason Crawford. We are commercializing therapeutic designer enzymes to degrade molecular damage that accumulates with aging. By addressing one of the hallmarks of aging, Revel is strategically positioned to develop therapeutics for multiple diseases of aging including osteoarthritis, kidney disease, cardiovascular disease, skin aging, and complications of diabetes.

See www.revelpharmaceuticals.com

About Kizoo

Kizoo provides mentoring and seed and early-stage financing with a focus on rejuvenation biotechnology. Having been entrepreneurs, VCs, and mentors in both high-growth tech and biotech companies for many years, with multiple exits and massive value created for the founders, Kizoo now brings this experience to the emerging field of rejuvenation biotech – a young industry that will eventually become much bigger than today’s largest technology markets.

As part of the Forever Healthy Group, Kizoo directly supports the creation of startups turning research on the root causes of aging into therapies and services for human application. Investments include AgeX, FoxBio, Turn.bio, Elevian, Oisin Biotechnologies, Underdog Pharmaceuticals, MAIA Biotechnology, and others.

Forever Healthy’s other initiatives include the evaluation of new rejuvenation therapies, evidence-based curation of the world’s cutting-edge medical knowledge, funding research projects on the root causes of aging, and hosting the annual Undoing Aging Conference.

For more information, please visit kizoo.com and forever-healthy.org

Frank Schueler
Managing Director, Kizoo Technology Capital GmbH
Amalienbadstr. 41, 76227 Karlsruhe
[email protected], +49 721 51600

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