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Harnessing the heterogeneity of aging
* Corresponding author: Warren Ladiges
Mailing address: Department of Comparative Medicine, School
of Medicine, University of Washington, Seattle, WA 98195, USA.
E-mail: wladiges@uw.edu
Received: 25 February 2021 / Accepted: 11 March 2021
DOI: 10.31491/APT.2021.03.048
Abstract
Genetic variation does not entirely address the consistent divergence of healthy and unhealthy aging in heterogeneous and homogeneous mammalian populations. The alteration of gene function through modification of histone DNA infrastructure is a logical extending explanation for this divergence. Since epigenetic alterations are reversible, therapeutic interventions that target the right gene or gene products could reverse aging, at the very least in the population of older people with poor health.
Keywords
Heterogeneity of aging, epigenetic alterations, reversing aging
Immortality is not a flesh and blood reality, since death is
inevitable. This is an issue that should not require much
scientific preponderance. However, it makes sense to focus on staying as healthy as possible with increasing age.
Healthy aging is a term used frequently to distinguish aging with relatively few disease complications, in contrast
to aging per se, which generally means unhealthy aging
and extensive disease complications. So why do some
people live longer than others, and some experience good
health in their later years compared to others that are
plagued with comorbidities?
In order to address this question, several factors need
to be considered. Genetic factors are at the forefront of
biogerontology research, and rightfully so, as genes code
for proteins that respond to stress in specific ways. Variations in genetic sequence can result in different ways of
responding to that stress, which may increase or decrease
aspects of healthy aging. Rare variants have been identified in centenarians that would appear to be natural therapeutic targets for enhancing healthy aging. However, it
seems precarious that aging in humans, a heterogeneous
population, is similar to aging in more homogeneous
populations. For example, certain inbred strains of laboratory mice have been shown to outlive other strains, yet
within each strain, there is the same biological divergence
of healthy and unhealthy aging groups with increasing
chronological age as seen in humans. This would suggest
there are additional factors to explain why some people experience healthy aging and others age poorly.
One possible explanation for this observation is epigenetic
influence. Epigenesis is the term used to describe the manner in which endogenous or exogenous factors can alter
gene function without direct changes in DNA structure.
Therefore, epigenesis is a constantly fluid process that
controls whether a gene or set of genes, under-performs or
over-performs. For example, histone deacetylase (HDAC)
is an epigenetic protein that shrinks the histone backbone that supports the DNA helix, thus repressing gene
transcription and coding of critical proteins involved in
healthy aging. Inhibition of HDAC would thus seem to
be a potential therapeutic target to enhance healthy aging.
There are likely a multitude of proteins that attack the
histone infrastructure that are not yet identified but have
a significant influence on gene function at critical times
over a lifespan.
The argument that epigenesis can alter gene function to
enhance healthy aging or accelerate unhealthy aging is a
logical argument but not yet scientifically proven. Extensive research in this area will be needed to determine how
the heterogeneity of aging can be harnessed to benefit
the health of older people. One very strong rationale for
moving in this direction is that epigenetic alterations are
reversible up to a point, meaning that therapeutic interventions that target the right gene or gene products could
reverse aging. Could this be a path toward longer life in
addition to healthier aging? Maybe, but at the very least, it
could be the promise of enhancing the lives of those older
people experiencing unhealthy aging.
Declaration
Acknowledgments
Supported by NIH grants R01 AG057381 and R01 AG067193 (PI, Ladiges).