Regular readers know that significant progress towards human rejuvenation, ending frailty and disease in aging, requires that SENS research, or something very like it, disrupts the present status quo to become the scientific mainstream in this field. SENS is focused on periodic repair of the fundamental damage to cells and macromolecules that occurs as a side-effect of the ordinary operation of metabolism. A strong focus here is on the accumulation of metabolic byproducts such as amyloids, lipofuscin and cross-links, while in comparison age-related changes in telomere biochemistry and epigenetic patterns are not all that important as targets: changes there are secondary effects, and thus should be reversed if the underlying damage is repaired.
In comparison the mainstream high level research strategy for aging and longevity is the other way around for these areas; there is comparatively little concern with metabolic byproducts as a target for treatment outside of the Alzheimer's field, and a great deal of interest in targeting telomeres and epigenetic changes. In general this is driven by a philosophy of metabolic alteration: the guiding principles are to (a) find ways to change the operation of metabolism to slow down the accumulation of damage and thus slow aging, or (b) force metabolic control processes back into a youthful configuration. This is a far worse approach than damage repair; it cannot produce rejuvenation, and in many cases ignores the root causes of aging while trying to force damaged biochemistry to behave as though it were not damaged and aged. We should expect only marginal outcomes from such efforts.
Both SENS and the present mainstream overlap in their concern for cancer and stem cell function. Both consider mitochondrial function important in aging, but with important differences in the present consensus of how and why it is important, and what should be done as a result. In the SENS vision, stochastic nuclear DNA damage is probably not all that important outside of cancer, but the mainstream consensus is that it probably is a cause of age-related disregulation of cellular activities and tissue function. This article reflects the mainstream view:
Age is the number one risk factor for myriad diseases, including Alzheimer's, cancer, cataracts, and macular degeneration. And while researchers are making progress in understanding and treating each of these ailments, huge gaps remain in our understanding of the aging process itself. The aging process can be traced down to the level of cells, which themselves die or enter senescence as they age, and even to the genomic level. Accumulation of mutations and impairments in DNA repair processes are highly associated with symptoms of aging. In fact, disorders that cause premature aging are typically caused by mutations in genes involved in the maintenance of our DNA. And at the cellular level, decreases in stem cells' proliferative abilities, impairments in mitochondrial function, and proneness to protein misfolding can all contribute to aging. As scientists continue to detail these various processes, the big question is, "At what step along all these pathways is the best place to intervene to try to promote healthy aging? The therapeutic goal would be to increase health span, not life span. There's nothing fun about living to be really old if your health diminishes to the point that it's no longer fun to be alive."
As DNA replicates, the cellular machinery involved in the process makes mistakes, leading to changes in the DNA sequence. While it's unclear exactly how DNA damage contributes to aging, what's certain is that the damage and mutations contribute to cancer, "There is this exponential increase in cancer risk during aging, so it's not at all unlikely . . . that accumulation of damage to the genome is really a major factor here." Premature-aging diseases in humans also point to the role of DNA repair and stabilization mechanisms in the aging process. But how DNA damage leads to aging in normal adults remains an open question.
Epigenetic marks shift over time in a variety of healthy cells. Indeed, mapping of DNA methylation in human cells has shown that some areas of the genome become hypermethylated with age, while others show reduced methylation. Histone modifications, another type of epigenetic mark, have also been shown to change with age in some human tissues. The question now is whether these epigenetic changes influence aging. "Is this an epiphenomenon that happens just because we age, or is it actually causing symptoms or diseases of aging and limiting life span?"
A particularly influential form of DNA damage occurs at telomeres, the repetitive sequences that cap chromosomes and shorten with age. While germ and stem cells express an enzyme called telomerase that replenishes telomeres, most cells' telomeres shrink with every division, due to the fact that DNA polymerase cannot fully replicate the ends of chromosomes. If the telomeres shrink too much or are damaged, cells undergo apoptosis or enter senescence. Telomere damage has clear effects on aging. Mice with short telomeres have diminished life spans and reduced stem-cell and organ function, while mice whose telomerase is enhanced in adulthood age more slowly.
Life depends on proper protein function. And proper protein function is all about proper protein folding. Misshapen proteins are often rendered useless and can clump together with other misfolded proteins inside cells. It is not yet clear whether protein misfolding leads to aging, but it appears that it is an almost inevitable physiological reality that the two coincide. To add insult to injury, advancing age also brings about the decline of molecular chaperones that aid in the folding process and of protective pathways that normally help clear misfolded proteins from cells. "The big open question is whether the accumulation of misfolded protein aggregates is the cause or consequence of the aging process. The hypothesis is that maybe there is a widespread accumulation of misfolded protein aggregates affecting all cells in the body, and that produces progressive dysfunction of cells in the body that leads to aging."
There is a new view of oxidative damage to mitochondria. "If damage is not too severe, there's some sort of protective response. What won't kill you makes you stronger." There is a limit to how much damage the organelle can handle, however, and mitochondrial dysfunction may well contribute to aging. "It's consistent with this idea that maybe from metabolism you get oxidative stress, you then get DNA damage, then that decline in mitochondrial function makes us age." Mitochondria's role in aging is likely not limited to oxidative or even DNA damage. Given the organelles' broad-reaching involvement in metabolism, inflammation, and epigenetic regulation of nuclear DNA. "They may be central integrators of many of the pathways we've implicated in aging."
Healthy adults produce about 200 billion new red blood cells each day to replace the same number removed from circulation every 24 hours. But the rate of blood-cell production declines with age. "It's a bit of a mystery as to why these self-renewing cells in different tissues stop working. The nature of molecular aging at the cellular level is not fully known." Researchers have also linked epigenetic alterations, such as locus-specific changes in DNA methylation, to the reduced regenerative capacity of stem cells with age. And age-related shifts in the environment in which stem cells divide and differentiate, dubbed the stem-cell niche, may also contribute to stem-cell aging. Exactly why and how stem cells slow down with age is still a mystery.
Stem cells and other cells that undergo damage and decline do not age in isolation. Researchers are finding that some processes of aging influence the release of regulators that circulate in the blood. "At one time, everybody thought, well, cells just get old and die. But the cells do more than just die. They do negative things, and they persist." One such regulator is growth differentiation factor 11 (GDF11), which measurably decreases with age. Researchers found that young blood can restore some lost functions in the hearts, brains, and skeletal muscles of older mice, and that these effects can be replicated by treating old mice with GDF11. The researchers are now working to pinpoint the sources of circulating GDF11, as well as to understand the mechanisms by which it remodels aging tissues.
Many of the questions voiced in the article could be answered most cost-effectively by implementing the SENS research programs to the point of demonstrating all of the repair biotechnologies in mice, and then observing the results. At this time it is estimated that the cost of doing so is about a decade of time and perhaps a billion dollars; this is about the same cost as is incurred in the development of a single new drug. It seems well worth doing.