Fresh as preprint (ref [7] across full text is the one originally posted)
Discovery of Thermodynamic Control Variables that Independently Regulate Healthspan and Maximum Lifespan
Kirill A. Denisov, Jan Gruber, Peter O. Fedichev
bioRxiv 2024.12.01.626230; doi: https://doi.org/10.1...24.12.01.626230
"The question, ”Can aging be modified, delayed, or reversed?” has profound social and economic
implications for rapidly aging societies today. Interventions, ideally, would intercept functional
decline and extend healthspan by delaying late-life morbidity (known as ”squaring the curve”).
These have proven elusive, but examples of differential aging in the animal world abound, suggesting
aging itself is a malleable process. We present a novel multi-scale theoretical framework
for entropic aging, and apply it to recently published DNA methylation data from 348 evolutionarily
distant mammalian species. Our analysis identified modules or correlated DNA methylation
changes associated with reversible pathway activation in key biological processes. We discovered
a single species-dependent scaling factor controlling the magnitude of fluctuations across biological
pathways. It acts as the organism’s ”effective temperature”, quantifying intrinsic biological noise
within networks and is unrelated to physical body temperature. Furthermore, we find a distinct
stochastic damage signature and an associated extreme value (Gumbel) distribution of activation
barriers controlling site-specific damage rates of individual CpG sites. This implies that aging is
driven by rare, high-energy transitions on rugged energy landscape, most likely simultaneous and
hence practically irreversible failures in highly redundant systems. While the overall rate of damage
accumulation and hence the maximum lifespan does not depend on the effective temperature driving
the noise in leading pathways, effective temperature does influence both initial mortality rate and
the mortality rate doubling time – thereby shaping the survival curve. Lowering effective temperature
must, therefore, be a promising Geroscience strategy, aimed directly at squaring the curve of
aging. The example shows that targeting the thermodynamic forces driving mammalian aging may
provide powerful strategies for the development of truly meaningful interventions to combat aging
in humans."
"...Our analysis suggests that critical actuarial aging parameters—
including the initial mortality rate and the
Gompertz exponent—are highly sensitive to the effective
temperature, thereby determining the difference between
maximum and average lifespan. Furthermore, targeting
the effective temperature must represent a powerful
strategy to extend healthspan by ”squaring the survival
curve.” Consequently, we advocate for the development
of a new class of longevity therapeutics that target these
thermodynamic forces underlying mammalian aging at
the macroscopic level. We assert that this approach is
the only viable strategy for enabling truly meaningful interventions
to combat aging in humans..."
"...It should be emphasized, however, that reducing effective
temperature does not impact the underlying rate
of aging. Consequently, efforts to extend healthspan
through effective temperature modulation will not inherently
slow the aging process and hence would not intercept
most of the functional decline associated with aging.
Aging in mammals appears to be a thermodynamically
irreversible process relying on the most fundamental biological
mechanisms. Further progress requires the investigation
of biological mechanisms behind thermodynamic
fidelity that could potentially be targeted pharmacologically.
This should open avenues for interventions aimed
at modulating the underlying drivers of mammalian aging
as a meaningful strategy to slow down the aging process
and produce a significant extension of human life..."
Edited by albedo, 13 December 2024 - 10:45 AM.
Screenshot 2024-11-06 140619.png 17.93KB
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