A complex systems approach to aging biology

Cohen, Alan A.; Ferrucci, Luigi; Fülöp, Tamás; Gravel, Dominique; Hao, Nan; Kriete, Andres; Levine, Morgan E.; Lipsitz, Lewis A.; Rikkert, Marcel G M Olde; Rutenberg, Andrew D.; Stroustrup, Nicholas; Varadhan, Ravi

doi:10.1038/s43587-022-00252-6

Cited by 104 publications

(68 citation statements)

References 146 publications

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“…Therefore, the rejuvenating effect of exercise and the aging effect of disuse are perhaps unsurprising, given that some of the age-related signal captured in the EWAS and TWAS meta-analysis of age reflect a decline in physical activity levels, rather than primary aging per se. This exemplifies the complex nature of aging biology, and highlights the challenge of assessing which factors mutually affect each other when causality becomes circular 47 (e.g. aging leads to a decline in physical activity/fitness levels, and a decline in physical activity/fitness levels leads to aging 48 ).…”

Section: Discussionmentioning

confidence: 95%

Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle

Voisin

Seale

Michaux

et al. 2022

Preprint

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Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late-life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta-analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle samples (n = 3,176). We show that: 1) individuals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, 2) exercise training leads to significant "rejuvenation" of molecular profiles, and 3) muscle disuse "ages" the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted towards a younger state after exercise training interventions, while the transcriptome shifted towards an older state after forced muscle disuse. We demonstrate that exercise training targets many of the age-related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity.

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Section: Discussionmentioning

confidence: 95%

Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle

Voisin

Seale

Michaux

et al. 2022

Preprint

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“…The same problem can be found with other entropic hypotheses, such as selfish evolution of mitochondria [ 20 ] or transposable elements [ 21 ], developmental hyperfunction [ 54 ], accumulation of glycation [ 55 ], somatic mutations [ 14 ], oxidation [ 11 ], telomere shortening [ 56 ], DNA damage [ 57 ], complexity-centered ideas [ 18 , 25 ] and others. Importantly, many of these processes may be relevant to senescence and are important to examine.…”

Section: “The Squirrel Test”mentioning

confidence: 88%

“…However, this review, while presenting a comprehensive list of observations, fails to provide a mechanistic explanation of why we age [ 24 ]. A subset of mechanistic hypotheses proclaims the complexity of biological systems as the central problem of aging research by reasoning that aging is wired into the inability of complex systems to sustain homeostasis [ 18 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Is Aging an Inevitable Characteristic of Organic Life or an Evolutionary Adaptation?

Lidsky

Yuan

Rulison

et al. 2022

Biochemistry Moscow

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Aging is an evolutionary paradox. Several hypotheses have been proposed to explain it, but none fully explains all the biochemical and ecologic data accumulated over decades of research. We suggest that senescence is a primitive immune strategy which acts to protect an individual’s kin from chronic infections. Older organisms are exposed to pathogens for a longer period of time and have a higher likelihood of acquiring infectious diseases. Accordingly, the parasitic load in aged individuals is higher than in younger ones. Given that the probability of pathogen transmission is higher within the kin, the inclusive fitness cost of infection might exceed the benefit of living longer. In this case, programmed lifespan termination might be an evolutionarily stable strategy. Here, we discuss the classical evolutionary hypotheses of aging and compare them with the pathogen control hypothesis, discuss the consistency of these hypotheses with existing empirical data, and present a revised conceptual framework to understand the evolution of aging. Electronic supplementary material The online version contains supplementary material available at 10.1134/S0006297922120021.

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“…To determine whether the road trip analogy can fit into existing conceptual insights on the integration of distinct cues during aging, I turn to a recent review by Alan Cohen and colleagues 6 . They identified ten input cues and eleven output consequences of aging, which they postulated could be connected through a limited set of cellular signaling pathways.…”

Section: The Length Correlation and Its Potential Role In Integrating...mentioning

confidence: 99%

The Road Less Traveled: Uncovering the Convergence Toward Specific Pleiotropic Phenotypes in Aging

Stoeger

2023

Preprint

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Aging is a complex process influenced by a wide range of environmental and molecular factors. Despite this complexity, individuals tend to age in highly similar ways, leading to the question of what drives this convergence. Recent research, including my own discoveries, suggests that the length of transcript molecules plays a crucial role in age-dependent changes to the transcriptome. Drawing inspiration from the road trip analogy of cellular transcription, I propose that a non-linear scaling law drives convergence towards specific pleiotropic phenotypes in biological aging. This scaling law is based on the notion that molecular changes observed during aging may reflect unspecific damage to cellular physiology. By validating this hypothesis, I can improve our understanding of biological aging and identify new candidate compounds for anti-aging interventions, as well as re-identify one known intervention. This work has actionable implications for improving human health and extending lifespans.

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A complex systems approach to aging biology

Cited by 104 publications

References 146 publications

Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle

Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle

Is Aging an Inevitable Characteristic of Organic Life or an Evolutionary Adaptation?

The Road Less Traveled: Uncovering the Convergence Toward Specific Pleiotropic Phenotypes in Aging

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