Q: A recent study out of Japan got a lot of coverage in the press, claiming to overthrow much of what was known about the role of mitochondria in aging. It is said to have found that mitochondrial mutations don’t really accumulate in aging cells over a lifetime. Instead, it found that age-related mitochondrial dysfunction is driven by “epigenetic” changes — changes in the “scaffolding” around DNA that helps regulate which genes are turned on and turned off. In particular, the investigators traced the effect back to the epigenetic downregulation of two genes involved in glycine production in mitochondria, such that providing them with glycine restored much of their normal function. Does this mean mitochondrial mutations really aren’t a problem and we can stop working to fix them?
A: The study is interesting, and contributes to a long-standing debate in this field about the frequency of specific mitochondrial DNA mutations with age and tissue type, and whether they contribute to specific diseases. It is clear at this point that michondrial dysfunction occurs with age and that damage in the form of mutations to mitochondria contributes to the diseases and disabilities of aging. We don’t believe that this particular study is actually a challenge to scientists’ existing understanding about how changes in mitochondria with age both drive and are driven by cellular and molecular damage, and the diseases and disabilities of aging. To maintain and restore youthful good health in aging people, it remains imperative to repair the cellular and molecular damage of aging directly, including alleviating the effects of large DNA deletions in aging mitochondria.
Development is Not Aging
In the study in question, the Japanese scientists compared cells from donors of two broad age groups: prepubescent (a fetus, a six-month-old, a six-year-old, and a twelve-year old) and older adult (ages 80-97). These donor demographics have somewhat limited utility in the context of aging studies, given that, among other issues, prepubescent children are still undergoing a great deal of growth and development. Cell division occurs in children vastly more rapidly than in adults, resulting in a continuous dilution of the cellular and molecular damage that drives degenerative aging changes. This is part of why you see no evidence of aging in children and young adults. On top of that, the researchers chose to study: fibroblasts, which are a kind of skin cell. Fibroblasts divide relatively slowly during adult life, but much more quickly during infant and child development. This presents a dramatic contrast with cells from a range of other tissues (such as neurons and skeletal and heart muscle cells) that don’t divide at all during adult aging, and whose cellular and molecular damage drive some of the most terrible degenerative diseases and debility we suffer in aging.
The second major problem is that during the years leading in to puberty, the child’s body is orchestrating a mind-bogglingly complex symphony of developmental changes, each of which involves altering the background expression of untold numbers of genes. Many of those changes are in turn under the control of epigenetic structures undergoing a series of carefully-regulated further changes that, of course, cease once a person exits puberty, completes their developmental cycle, and reaches their adult proportions.
For these reasons, it’s long been understood by biogerontologists that to unravel the drivers and effects of degenerative aging, scientists must study the cells and tissues of animals that have completed childhood and adolescent development. It is not merely premature, but unsound from first principles, to conduct studies in rapidly-dividing cells undergoing dramatic, regulated epigenetic changes, and draw lessons from them regarding what happens to aging cells in tissues that either don’t divide at all, or divide much more slowly, and that are long past their developmental period. Unfortunately, this understanding has been underappreciated by scientists from non-biogerontology specializations, leading to many studies being designed and interpreted inappropriately for purposes of understanding and intervening in degenerative aging.
Mitochondrial Mutations: Rare, Yet Crippling
Now let us take one step back. What is actually known about the frequency and impact of specifically age-related mitochondrial mutations? First, in line with the ability of dividing cells to dilute out structural damage, multiple studies in aging rodents and humans report that the mutations in mitochondria that persist in cells and thus accumulate with age are confined almost entirely to cell types that don’t divide during adulthood (e.g., brain neurons, heart muscle cells, and skeletal muscle). Second, those mutations are quite surprisingly rare: even in tissues that are actually affected by mitochondrial mutations with age, fewer than 1% — and perhaps as few as 0.1% — of cells are found to be affected.,
Still, the evidence suggesting that this damage drives degenerative aging is powerful,,,, The level of oxidative damage to mitochondrial DNA, the rate of accumulation of mitochondrial DNA mutations with age, and the structural vulnerability to such mutations are collectively robustly correlated with species maximum lifespan (the strongest integrative measure of the overall rate of aging in a species).,, Remarkably, this has recently been demonstrated even in rockfish, whose senescence is nearly negligible: lifespan in rockfish species was found to correlate negatively with the rate of mutation of their mitochondrial, but not nuclear, genomes — a relationship that the investigators’ analysis suggested was not likely to be an artifact of tradeoffs with fecundity or the rate of germline DNA replication. Calorie restriction (the most robust intervention that slows the rate of aging in mammals) lowers the rate of accumulation of mitochondrial deletion mutations with age.,,,, And when mice are given a transgene that directs a form of the antioxidant catalase directly to their mitochondria — an enzyme that complements the existing antioxidant machinery in the mitochondria in a way that reduces total mitochondrial DNA oxidative damage, including but not limited to deletion mutations — it extends their mean and maximal lifespan and ameliorates multiple pathologies of aging., Yet no such effects are observed when the same enzyme is directed to sites outside of the mitochondria, or when other antioxidant enzymes are expressed elsewhere in the cell,, or even when non-complementary enzymes are sent to the mitochondria.
The resolution of this paradox — the strong link between mitochondrial DNA deletions and the rate of degenerative aging, in the face of the rarity of such mutations — is the heart of SENS Research Foundation Chief Science Officer Aubrey de Grey’s Cambridge PhD thesis, which was later published with minor modifications as The Mitochondrial Free Radical Theory of Aging in 1999. A key chapter entitled “The Search for How So Few Anaerobic Cells Cause So Much Oxidative Stress” put the seemingly-opposing findings this way:
The apparently low level of mutant mtDNA [mitochondrial DNA] even in very elderly individuals was perhaps the most powerful argument, in 1995, against the idea that mtDNA decline is central to aging. … [M]itochondria undergo a functional decline far in excess of the level of mutation, and [some have] inferred that mtDNA damage could therefore not be the cause of this decline. Looking at it another way: we knew that cells can survive quite well with only a fairly small proportion of functioning mitochondria. Therefore, the natural inference was that a similar level of overcapacity would exist on a larger scale … [I]t certainly seemed unreasonable to suppose that the body should encounter much difficulty if, say, only 1% of its cells are anaerobic, unless there is some other source of oxidative stress. Thus, the question of just how few cells were anaerobic in elderly people seemed to be an acid test of [the mitochondrial free radical theory of aging]—as it stood then.
Mitochondria and Aging: Where You Stand Depends On Where You Sit
There are two broad kinds of resolution to this paradox. The first is the tissue-specific one. Although cells overtaken by mitochondria bearing DNA deletions are rare, they can have powerful effects on health in tissues where they are unusually enriched in critical cell types, particularly if relatively few of those cells exist in the first place. Such is the case for the key dopamine-producing neurons in an area of the brain known as the substantia nigra pars compacta (SNc). SNc dopaminergic neurons are much more vulnerable to being overtaken by mitochondria bearing large deletions in their DNA than are other cell types in the brain,,,, and such mutations clearly drive dysfunction, including being tightly liked to Parkinson’s disease.,, The same high regional vulnerability to mitochondrial DNA deletions occurs in people suffering with non-Parkinson movement disorders and even in “normal” aging brains, albeit at a lower rate, and yet the finding has no parallel in the smaller and less harmful point mutations.
The other kind of tissue-specific effect relates more to the unique properties of the affected cell type itself, with the cardinal case in this category being skeletal muscle. Unlike most cell types, skeletal muscle “cells” are not isolated from all of their neighbors by a membrane. Instead, the long stretches of skeletal muscle fibers are comprised of multiple segments, each of which contains its own nucleus, which is in turn supported by a local population of mitochondria, with additional mitochondria in the membrane-bound space outside the fiber itself. Mitochondrial DNA deletions not only accumulate with age at a faster pace in skeletal muscle than in many other aging tissues,,, but because of that structure their effects are much more catastrophic. When a local nucleus’ mitochondrial population is overtaken by deletion mutations, the segment first atrophies at that point, and then fails, leading the fiber to split or break locally and ultimately causing the loss of the entire fiber. These processes — loss of energy production and the splitting and loss of fibers — are a key driver of sarcopenia, the age-related loss of skeletal muscle mass and function that occurs even in lifelong master athletes.
Because deletion mutations in mitochondrial DNA are core molecular lesions driving these diseases, repair of these mutations will be central to their prevention, arrest, and reversal. But you can’t tell that from a study of skin cells.
Mitochondria and Aging: Not What Is Inside the Cell, but What Comes Out of It
Preliminary evidence supporting direct involvement of mitochondrial mutations in Parkinson’s and sarcopenia was already extant when Dr. de Grey wrote his thesis, and was duly noted. But Dr. de Grey’s thesis focused on the broader and more indirect harm that these rare, isolated cells’ deletion-bearing mitochondria play in the aging body as a whole. Only a very small number of cells accumulate significant mitochondrial mutations with aging — and yet, one sees widespread abnormalities in mitochondrial function across many tissues in aging people and experimental animals, and a rise in oxidative stress all across the body (long been assumed attributable to mitochondrial free radicals, but resulting from a “vicious circle” mechanism that no longer fits the experimental data and that is largely discredited today.,,).
Dr. de Grey’s solution to those paradoxical findings is too complex to delineate here; readers are encouraged to consult Dr. de Grey’s thesis adaptation or Chapter 5 of Ending Aging for details. In very broad terms, his work provides a detailed mechanism to explain how a very small number of cells taken over by mitochondrial deletions can spread oxidative stress throughout the entire body.
Deletion mutations completely shut down the cell’s ability to rely on oxidative phosphorylation, because they prevent their mitochondria from producing their share of the proteins that comprise its machinery. Denied the ability to generate energy through the most productive and efficient route, such cells are forced to undergo metabolic adaptations that result in the export of electrophilic wastes that in turn spread oxidative stress to remote and otherwise-healthy cells. This solution explains many seemingly-unrelated phenomena observed in aging tissues, and resolves paradoxes in the literature of mitochondria and aging. Furthermore, many of its key predictions have subsequently been confirmed by new or more dispositive experimental findings.,,,,,,,,,
In turn, this solution — that local damage to mitochondrial DNA spreads oxidative stress to remote and otherwise-healthy cells — helps to explain the incidence of widespread mitochondrial dysfunction in aging cells, even if their mitochondria’s DNA is still pristine, or damaged in ways that are not yet fixed into the irreversible state of a mutation.,
Of course, it is far from the only factor: mitochondria are dynamic organelles, which adapt their activity to respond to differences in fuel quantity and quality, redox status, energy demands, and dynamics, as well as being at the center of cellular processes such as apoptosis (cellular suicide). Thus, as the cellular and systemic environment changes, so necessarily must mitochondrial function. It is therefore unsurprising that many forms of the cellular and molecular damage of aging drive deviations in mitochondrial function from the healthy norm of youth.
For example, mitochondria have emerged as key components of the cellular senescence program. Thus, when cancer-promoting mutations and other forms of aging damage arise in aging cells, mitochondria with perfectly intact genomes will respond appropriately by initiating and effecting the protective shutdown of growth in these “risky” cells.,, This change in behavior would not be triggered in young cells with intact genomes, where it would be entirely pathological instead of part of a medium-term survival strategy.
Conversely, rising insulin resistance with age, independent of body fat, appears to be driven by the secretions of senescent preadipocytes (the stem-like precursors of fat cells) in key fat depots. Because insulin resistance leads to aberrant mitochondrial function (see below), ablation of these senescent cells can be expected to restore insulin sensitivity — a prediction for which some preliminary proof-of-concept has recently been generated.
In another example, deficits in energy production associated with changes in the levels and activity of mitochondrial components occur very early in the process that ends in Alzheimer’s disease, and significant experimental evidence suggests that this is driven by soluble intracellular aggregates of beta-amyloid protein,,,,,,,,, which combined with the later extracellular aggregates (the so-called plaques) are one of the key pathological drivers of the disease and of “normal” cognitive aging.
And again, rising oxidative stress from accumulating numbers of cells bearing deletion mutations in their mitochondria can trigger aberrant mitochondrial function in cells whose own mitochondrial DNA remains intact.,
Confounding matters further, some of these same functional deviations can also occur for reasons that are partially or completely independent of age, but that are often overlaid upon the primary aging process. Such age-independent phenomena can often be reversed by lifestyle changes or medication: such is the case for changes in mitochondrial function due to overweight and obesity (reversible with exercise and/or weight loss via diet, or bariatric surgery), insulin-resistant states (often substantially reversible with some medications and often with weight loss and/or exercise,), or sedentary lifestyle (reversible by spending less time on the couch,).
Others, even if driven originally by aging damage, can be ameliorated by pharmacological or lifestyle means. For instance, the decline in estrogen levels associated with menopause can be treated with exogenous hormones, and this can partially normalize mitochondrial changes that are due to the loss of those same hormones, even if the original aging processes responsible for those declines are not affected., (The same is evidently not true of testosterone replacement in the aging male, however).
Of course, the effects of lifestyle, environment, and genetics don’t happen independently of one another, or of the central aspects of aging that are driven by aging damage itself. Thus, many of the effects of aging are amplified by — or lead to similar clinical outcomes as — poor lifestyle, so that lifestyle changes can often make an average sedentary, moderately overweight older person’s mitochondrial function look more like that of an average sedentary, moderately overweight person who is many years younger. This in turn leads to some muddied thinking in the press, resulting in misleading headlines about exercise or weight loss “reversing aging.” To actually reverse aging, one can’t just limit the amount of surplus damage one’s lifestyle imposes in one’s tissues: one must repair the lesions that aging and lifestyle alike have already inflicted on our tissues, after they have already formed. Doing this is the essence of rejuvenation biotechnology.
Cancer: the False Immortality
Decades ago, scientists began to refer to the unlimited proliferative potential of cancer cells as “immortalization”. This terminology both illuminates and muddies aspects of the road to a future free of age-related disease. The key finding in this new research is the epigenetic silencing of nuclear genes governing the mitochondrial serine/glycine biosynthesis pathway in cells from older (fully-developed) donors. On the supposition that these findings actually reflect phenomena that occur in some aging cells (and as we have seen, the publication as it stands cannot disaggregate aging proper from growth and development), some have leapt to conclusions about their implications for intervention in the aging process without duly bearing in mind the adaptive nature of gene expression, or the central reality that cellular and molecular damage is the ultimate driver of all aging changes, whether adaptive or pathological. In their perfectly rational eagerness for a fast solution to the wicked challenges of degenerative aging, some have grasped for pharmacological or other means to force aging cells to behave more like the “young” (or rather, immature) cells used in this paper. There is significant evidence that this, too, is a Pyrrhic route to “immortality.”
In the last five years, powerful genomic and metabolic control analysis methods have rapidly discovered the upregulation of this same serine-glycine metabolic pathway in several kinds of cancer, where it supports energy production, maintenance of redox status, and the synthesis of raw materials for replicating their DNA, particularly in cancer microenvironments where oxygen availability is limited.,,,,,,,, One study estimated that “about 28% of lung-, 19% of breast-, 9% of prostate-, 30% of colorectal-, 23% of brain- and 21% of ovarian cancers manifest a significant upregulation (P<0.05)” of the serine-glycine pathway. Amongst other findings, higher activity of these genes in patient tumor biopsies has been found to mark more invasive tumors and worse outcomes for patients, and more rapid proliferation of cancer cell lines.
In one notable study, overexpression of any of several genes in the serine/glycine pathway, including both of the nuclear-encoded mitochondrial genes SHMT2 and GCAT central to the new Japanese collaboration, was sufficient to transform telomerase-expressing but otherwise normal fibroblasts into cancer stem cells that would spontaneously form tumors in vivo in lab animals. Conversely, interfering with the same mitochondrial glycine biosynthesis genes preferentially impaired the more rapidly-proliferating cancer cells. When gene silencing techniques were used to keep the SHMT2 protein from being produced in these cancer cells, their growth was shut down — only to be restored by supplying glycine in the medium. And in a striking coincidence, the concentration the investigators used to rev the cancer cells’ growth back up again was the same (140 μM) as the researchers in the Japanese collaboration had used to supplant the gene’s activity in fibroblasts from old donors.
Assuming that the Japanese group’s findings do hold up, why might these genes be so active in fibroblasts from fetuses and prepubescent children? One possible explanation is that intense activity in the serine-glycine biosynthesis pathway is necessary to support the rapid growth required to develop a young child, just as it is necessary to support the growth of some cancers. In turn, key genes in this pathway would be epigenetically silenced in adults when growth is complete — both because they are no longer needed, and because of the looming risk of cancer in adult cells. But of course, evaluation of this hypothesis — or indeed any other possible interpretation of the new study — requires additional data from fibroblasts from young adult and middle-aged comparison groups, and cells from postmitototic tissues, to contextualize findings in the “young” and the aged donor groups in the original study.
Suture the Wound Before Releasing the Tourniquet
There are no quick fixes to the problem of mitochondrial malfunction with age, or the many other wicked ways that aging bodies are made to fall apart over time. Mitochondrial mutations will need to be obviated to restore youthful health and vitality, but repair of that damage alone will not be sufficient to restore normal mitochondrial function, let alone the overall health typical of a young person in his or her prime. The cellular and molecular damage driving degenerative aging is multifarious, and interacts on multiple levels to entrap aging bodies in an accelerating trajectory down into increasing ill health. The vision of a future free of the disease and debility of aging can only be realized when rejuvenation biotechnology is applied to all forms of aging damage, restoring our tissues to proper structural and functional integrity.
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