Aging, or senescence, is the gradual deterioration of biological capability as a function of
age. Though lower organisms, such as bacteria and even some plants, exhibit immortality in some
capacity (negligible senescence or clonal immortality), most organisms characterized by a high
degree of complexity and organization do inevitably age. Aging has been a reality and source of
anxiety in human societies for millennia, and while no intervention has shown any demonstrable
ability to halt or reverse the aging process, several modern experimental avenues have slowed
down certain indications of aging in the laboratory setting, or otherwise generated organismal
strains with greater-than-normal lifespans.
Two modalities of cellular aging can contribute to the overall aging of the organism. The
first of these is damage-based, wherein the effects of aversive environmental stimuli accumulating
over the course of a lifetime cause a loss of function. This impairment is accidental, if occasionally
unavoidable, and includes damage by way of ultraviolet light and oxidative stress on the
biomolecular machinery of mitochondrial or genetic material. The second of these routes is
programmed aging, coded by genetic markers to reduce the capability of older members. While
potentially unsettling, the notion of aging as a selected-for, beneficial trait in a population is well
founded; aged family members can contribute to the rearing of new offspring without reproducing themselves, and their eventual deaths liberate resources, ultimately increasing the average fitness of the group.
Anti-aging experiments, therefore, will seek to act upon one of these routes. Less research
has been invested into affecting the damage-based route of aging, simply because avoidance of the
aversive stimuli appears more effective than reversing their effects, and because the effectiveness
of antioxidant foods (i.e. blueberries, nuts, etc.) is inconclusive in life-extension, despite their
theoretical capacity to limit the damage of oxidative stress at the cellular level. Far more promising
is the potential of reversing programmed cellular senescence. Several cellular pathways have been
implicated in the process, including telomere shortening, the mTOR autophagy pathway as
implicated by calorie intake and restriction, epigenetic DNA modification, to name a few.
Telomeres are one of the more popular cellular components to be associated with aging.
Telomeres are sections of noncoding or ‘junk’ genetic material deposited at the end of each
chromosome. These junk sections become relevant because the genetic replication cycle is
startlingly flawed. During the replication event, the enzymes responsible for duplicating the DNA
operate such that a small amount of genetic material is cut off and lost at the end of each strand.
The telomeres act as disposable buffers to this process, being truncated with every cycle, and while
newborns and children contain an enzyme which rebuilds these sections (telomerase), the enzyme
is notably absent at effective concentrations in adults. The theory goes on to suggest that when the
telomeres are totally exhausted, the coding portions of DNA begin being cut into, are
compromised, and then losses of function ensue. This makes telomere shortening an attractive
early target for programmed aging; if the telomeres can be extended in adults or telomerase
reactivated, perhaps the necessary genetic material could be kept safe. However, while Richard
Cawthon in 2003 discovered that those with longer telomeres tend to live longer than those with
short telomeres, it not known whether short telomeres signify of cellular age or truly contribute to
the aging process. Further research by Nordfjäll in 2009 and Biasco earlier in 1997 demonstrated
that mice lacking the telomerase enzyme even as newborns do not suffer shorter lifetimes, and that
while most humans experience this telomere truncation, a third of participants paradoxically
showed no telomere shortening as they aged, though age they did nevertheless. Additional
telomere research would be required to establish a biomolecular clock therein.
Figure 1. Telomere Shortening Diagram Figure 2. mTOR Pathway Schematic
Mainous, American Journal of Hematology, Garciá-Arencibia, Seminars in Cell & Developmental 2013
Figure 3. DNA Methylation Diagram Figure 4. Rim15/Ras2 Is Required for Chronological Life
Span Extension and Cellular Protection
201308epigenomics/14carc01_1.html Wei, PLoS Genet, 2008
A second cellular pathway is implicated with calorie restriction. The restriction of caloric
intake leads to longer lifespans, in a manner that is unrelated to the various metabolic disorders
caused by overeating. While the cause of the effect that is unclear, researchers lead by Fontana in
2010 found that it is likely mediated by the nutrition sensing function of the mTOR pathway.
mTOR is a protein that inhibits autophagy, the degradation of the cell by the cell. Researchers
found that when organisms restrict their diet, mTOR activity is reduced, which causes an increased
of autophagic behavior. Despite it being a degradation of the cell, autophagy is a controlled
degradation that increases longevity, as the cell parts degraded through autophagy are recycled and
regrown. This prevents the cell from entering ‘benign senescence,’ a non-functional state that
secretes various toxic agents, and may cause the losses-of-function associated with aging. Caloric
restriction of 70% of what would be consumed at the pleasure of the organism cause these positive
effects. Researchers hypothesize that the restriction decreases mTOR activation through insulin
sensitivity, as mTOR has been shown to impair spikes of glucose concentration in the blood.
Therefore, longevity may be associated with caloric restriction and insulin sensitivity by inhibiting
mTOR, which in turns allows autophagy to occur more frequently. As suggested by Johnson in
2013, inhibition of the mTOR pathway would additionally reduce levels of reactive oxygen species
on the body, which otherwise could damage genetic material. Additionally, a variation in the gene
FOXO3A has a positive effect on the life expectancy of humans, and is found frequently often in
people living beyond 100 years of age, regardless of geographic location. FOXO3A acts on the
sirtuin family of genes which Ghosh in 2013 demonstrated to inhibit mTOR.
There is also a strong correlation of DNA methylation with age. Methylation is a type of
epigenetic modification, wherein genetic information is modified on a continual basis, rather than
being locked-in at conception. Horvath hypothesized that DNA methylation, which deactivated
sections of the genome, might represent cumulative effect of an epigenetic maintenance system
intended to gradually shut down the functional capabilities of the cell. Christensen in 2015 noted
that DNA methylation age of blood predicts all-cause mortality in later life. Furthermore, Occampo
in 2016 found that mice aged prematurely can be rejuvenated to a younger phenotype and their
lives extended by up to 30% by partially ‘resetting’ the methylation pattern in their cells (as a full
methylation reset lead to immortal cancerous cells). This resetting into a juvenile state was
experimentally achieved by activating the four DNA transcription factors (Sox2, Oct4, Klf4 and
c-Myc) which have used for producing young animals from cloned adult skin cells. This epigenetic
research is promising in offering a great degree of control in the experimental manipulation, though
invading and demethylating various tissues in a living human presents its own difficulties.
There are several miscellaneous pathways and experimental modalities that may be
implicated in aging reversal. For example, a decreased Growth Hormone/Insulin-like Growth
Factor-1 signaling pathway is associated with increased life span in fruit flies, nematodes and mice.
The precise mechanism by which decreased GH/IGF-1 signaling increases longevity is unknown,
but various mouse strains with decreased GH and/or IGF-1 induced signaling share similar
phenotypes, including increased insulin sensitivity, enhanced stress resistance and protection from
carcinogenesis. As found by Junilla in 2013, the studied mouse strains with decreased GH
signaling showed between 20% and 68% increased longevity, and mouse strains with decreased
IGF-1 induced signaling revealed a 19 to 33% increase in life span when compared to control mice.
Additionally, the Ras2 gene may be similarly implicated. Excitingly, Wei found in 2008 that a
yeast mutant lacking the genes sch9 and ras2 showed a tenfold increase in lifespan under
conditions of calorie restriction. This is the largest increase achieved in any organism, yeast though
it might be. Lastly, UNSW researchers under Jun Li in 2017 have manipulated the cellular repair
factor NAD+ and achieved frog age-reversal, stating that human trials will begin in three months
at the time of writing.
Crossing the space from laboratory models, be they in vivo or in vitro, to human beings
presents a salient difficult in longevity research. For that reason, long-term longitudinal studies
offer the best ideas on what might affect change. Many aspects of programmed cell aging have
been isolated and are being worked on currently, and as the data continues being brought to light,
the picture will likely resolve. One certain thing, however, is that the various anti-aging creams,
tonics, or unguents that make their rounds through infomercials are either based entirely on
pseudoscience or attack the cellular components of aging in a limited and ultimately ineffectual
way. In any case, for now, the challenge of longevity remains an enigma for longevity researchers
themselves and the bioethicists that may oppose them.
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