Rapamycin Rules out DNA Damage Theory of Aging

Dr. Mikhail Blagosklonny gleans an important new discovery in aging research—deduced from recent studies on short-lived mice and rapamycin.

3D illustration of a mutated or damaged DNA strand

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The exact mechanisms at play in the human aging process are still up for debate. A number of great minds in science have proposed plausible aging mechanisms and theories, such as DNA damage, telomere shortening, and DNA damage theories of aging. DNA damage theories suggest that aging is functional decline, caused by the accumulation of molecular damage. However, some scientists counterclaim that neither DNA damage nor telomere shortening limit lifespan or cause aging.

Dr. Mikhail Blagosklonny—an adjunct faculty member at the Roswell Park Comprehensive Cancer Center and Editor-in-Chief at Aging, Oncotarget, Oncoscience, and Cell Cycle—gleaned an important new perspective from recent aging studies, which could have been overlooked. He expanded on this discovery in a recent research perspective that was published in February 2021 in an issue of Aging, entitled: “DNA- and telomere-damage does not limit lifespan: evidence from rapamycin.” To date, this research paper has generated an Altmetric Attention score of 43.

Rapamycin is a macrolide antibiotic that has immunosuppressive properties, regulates a key cellular growth pathway (mTOR), and has been at the center of numerous studies of aging since its discovery in 1964. Dr. Blagosklonny explains that, based on findings from recent mouse-model studies of rapamycin’s effects on short-lived mice, normal aging is not caused by the accumulation of molecular damage or telomere shortening.

“Here I discussed new evidence that normal aging is not caused by accumulation of molecular damage or telomere shortening: while extending normal lifespan in mice, rapamycin failed to do so in mice dying from molecular damage (Figure 1).”

Evidence From Rapamycin

In the study which Dr. Blagosklonny refers to, researchers genetically modified mice to artificially shorten telomeres, administered rapamycin to normal mice and the telomerase-deficient short-lived mice, and observed the effects. In normal mice, results were congruent with a number of other studies that found lifespan was significantly extended. In the telomerase-deficient mice, lifespan was shortened as a result of rapamycin. 

“While shortening lifespan by 18% in unnatural telomerase-deficient mice, in the same study in natural mice, rapamycin increased lifespan by 39% and healthspan by 58% (measured as tumor-free survival) [3].”

Given that rapamycin prolongs life in normal mice, Dr. Blagosklonny asserts that this study proves that normal lifespan is not constrained by telomere length. Telomeres only become life-limiting when they are artificially shortened to the point where rapamycin can no longer extend lifespan. Furthermore, Dr. Blagosklonny explains that although molecular damage and telomere shortening could be life-limiting, they ultimately do not limit life because quasi-programmed aging occurs at a faster rate.

“Although molecular damage accumulates, this accumulation is not life-limiting because quasi-programmed aging terminates life first (Figure 1A). Quasi-programmed (hyperfunctional) aging is life-limiting, because it is favored by natural selection.”

Quasi-Programmed (Hyperfunctional) Aging

In 2012, Dr. Blagosklonny wrote another widely-read research perspective that explains in great detail what his proposed hyperfunction theory of aging is, entitled, “Answering the ultimate question “What is the Proximal Cause of Aging?

“According to hyperfunction theory, aging is quasi-programmed, a continuation of developmental growth programs, driven in part by hyper-functional signaling pathways including the mTOR pathway [9].”

He explains that hyperfunction is an excessive, yet normal function that occurs later in life. Hyperfunction in this context does not necessarily mean an increase in function and, in some cases, it even means a decrease in function. The same pathways and functions that drive growth and development earlier in life, also drive age-related diseases later in life. Dr. Blagosklonny proposes that quasi-programmed (hyperfunctional) aging is favored by natural selection and is what limits life.

“It is hyperfunctional signaling pathways such as mTOR (one of many) that drive both growth and aging, causing age-related diseases that in turn damage organs, leading to secondary loss of function.”

Many signaling pathways interact with mTOR to drive aging, forming a network, including MEK/MAPK, NF-kB, p63, HIF-1, and many others. Dr. Blagosklonny suggests that, in theory, there could be a number of mTOR-independent factors of quasi-programmed aging that are life-limiting, as well. He goes on to exemplify several lines of evidence concluding that it is not molecular damage that causes normal aging or limits life—it is normal, quasi-programmed (hyperfunctional) aging.


Dr. Blagosklonny mentions a forthcoming review that will be entitled: “When longevity drugs do not increase longevity: Unifying development-driven and damage-induced theories of aging.”

“Once again, damage accumulates and must cause death eventually, but quasi-programmed (hyperfunctional) aging terminates life first. Molecular damage can become life-limiting, when artificially accelerated or, potentially, when quasi-programmed aging is decelerated.” 

Click here to read the full research perspective, published in Aging.

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