Molecular damage in aging

Gladyshev, Vadim N.; Kritchevsky, Stephen B.; Clarke, Steven; Cuervo, Ana María; Fiehn, Oliver; Magalhães, João Pedro de; Mau, Theresa; Maes, Michal; Moritz, Robert L.; Niedernhofer, Laura J.; Schaftingen, Emile Van; Tranah, Gregory J.; Walsh, Kenneth; Yura, Yoshimitsu; Zhang, Bohan; Cummings, Steven R.

doi:10.1038/s43587-021-00150-3

Cited by 64 publications

(33 citation statements)

References 150 publications

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“…An age-related increase in molecular damage is the cornerstone of aging 1 . This damage manifests in many forms, such as damage to metabolites, DNA and proteins 43 . Although gene expression analyses have been a major tool in examining the underlying biology of aging and available data far exceeds other “omics” (e.g.…”

Section: Discussionmentioning

confidence: 99%

Deterioration of the human transcriptome with age due to increasing intron retention and spurious splicing

Mariotti

Kerepesi

Oliveros

et al. 2022

Preprint

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Adult aging is characterized by a progressive deterioration of biological functions at physiological, cellular and molecular levels, but its damaging effects on the transcriptome are not well characterized. Here, by analyzing splicing patterns in ~1,000 human subjects sampled across multiple tissues, we found that splicing fidelity declines with age. Most prominently, genuine introns fail to be spliced out, manifesting as a broad surge in intron retention, and this is exacerbated by the increase in diverse spurious exon-exon junctions with age. Both of these effects are prominently detected in the majority of human tissues. Collectively, they result in the progressive deterioration of the active transcriptome, wherein functional mRNAs are increasingly diluted with non-functional splicing isoforms. We discuss the concept of "splicing damage" and formulate methods to quantify it. Using these tools, we show that splicing damage increases both with age and with the incidence of diseases. Altogether, this work uncovers transcriptome damage as a critical molecular indicator of human aging and healthspan.

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Section: Discussionmentioning

confidence: 99%

Deterioration of the human transcriptome with age due to increasing intron retention and spurious splicing

Mariotti

Kerepesi

Oliveros

et al. 2022

Preprint

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“…Many irreversible chemical events, including protein denaturation, oxidation, and DNA mutation 23 , degrade cells, but most of this damage is flushed away by mitosis, when 50% or more of the cell’s components are made anew, and genome repair occurs. 24 This concept of cell repair by dilution with new materials made at mitosis, thus driving “the cause of aging and control of lifespan”, was articulated by Gladyshev, 25 expanding Sheldrake’s general suggestion, 26 and Hirsch’s mathematical examination. 27 As Ferrucci noted: “Aging is the ratio between damage accumulation and compensatory mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…Lifespan is correlated with an age when fewer than one-in-a-thousand cells are dividing, quantifying the long-appreciated mechanism of aging, the failure of cells to be rejuvenated by dilution with new materials made, and DNA repaired, at mitosis. 24-26 These observations provide practical mathematical expressions for comprehending, and managing, the challenges of growth and aging, for such tasks as improving the effectiveness of COVID-19 vaccination in the elderly.…”

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confidence: 99%

“…Here we show, by examining growth and lifespan in units of numbers of cells, N, (Cellular Phylodynamics 6 ), that both processes are linked to the same reduction in the fraction of cells dividing, occurring by a simple expression, the Universal Mitotic Fraction Equation .Lifespan is correlated with an age when fewer than one-in-a-thousand cells are dividing, quantifying the long-appreciated mechanism of aging, the failure of cells to be rejuvenated by dilution with new materials made, and DNA repaired, at mitosis. [24][25][26] These observations provide practical mathematical expressions for comprehending, and managing, the challenges of growth and aging, for such tasks as improving the effectiveness of COVID-19 vaccination in the elderly.…”

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confidence: 99%

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On How, and Why, and When, We Grow Old

Citti

Michaelson

2022

Preprint

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Growth and aging are fundamental features of animal life. The march from fertilization to oblivion comes in enormous variety: days and hundreds of cells for nematodes, decades and trillions of cells for humans. Since Verhulst (1838) proposed the Logistic Equation (exponential growth with countervailing linear decline in rate), biologists have searched for ever better density dependent growth equations, none which accurately capture the relationship between size and time for real animals. Furthermore, while growth and aging run in parallel, whether the relationship is causal has been unknown. Here we show, by examining growth and lifespan in units of numbers of cells, N, (Cellular Phylodynamics), that both processes are linked to the same reduction in the fraction of cells dividing, occurring by a simple expression, the Universal Mitotic Fraction Equation. Lifespan is correlated with an age when fewer than one-in a-thousand cells are dividing, quantifying the long-appreciated mechanism of aging, the failure of cells to be rejuvenated by dilution with new materials made, and DNA repaired, at mitosis. These observations provide practical mathematical expressions for comprehending, and managing, the challenges of growth and aging, for such tasks as improving the effectiveness of COVID-19 vaccination in the elderly.

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“…Aging is also associated with a reduced ability to re-entrain to a new light/dark cycle, and increased mortality following repeated “jet lag” (Davidson et al, 2006; Inokawa et al, 2020; Sellix et al, 2012). It can be posited that circadian attenuation likely contributes to increased damage accumulation (Gladyshev et al, 2021), frailty phenotypes (Fried et al, 2021) and decreased resilience seen with aging (Kirkland et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Defining the age-dependent and tissue-specific circadian transcriptome in male mice

Wolff

Gutierrez‐Monreal

Meng

et al. 2022

Preprint

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SUMMARYCellular circadian clocks direct a daily transcriptional program that supports homeostasis and resilience. Emerging evidence supports age-associated changes in circadian functions. To define age-dependent changes at the systems level, we profiled the circadian transcriptome in the hypothalamus, lung, heart, kidney, skeletal muscle, and adrenal gland in 3 age groups. We found age-dependent and tissue-specific clock output changes. Aging reduced the number of rhythmically expressed genes (REGs), indicative of weakened circadian control. Many genes gained rhythmicity in old tissues, reflecting an adaptive response. REGs were enriched for the hallmarks of aging, adding a new dimension to our understanding of aging. Differential gene expression analysis found that there were temporally distinct clusters of genes in tissue-specific manner. Increased daily gene expression variability is a common feature of aged tissues. This novel analysis extends the landscape of the understanding of aging and highlights the impact of aging on circadian clock function and temporal changes in gene expression.HIGHLIGHTS- Rhythmically expressed genes (REGs) in Young, but not Old mice, are enriched for the aging hallmarks across all tissues.- The numbers of REGs decline across all tissues with age implicating the circadian clock in altered homeostasis.- Age- and tissue-specific differentially expressed genes (DEGs) cluster at specific times of the day.- Increase in gene expression variability over a day is a common feature of aging tissues.

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Molecular damage in aging

Cited by 64 publications

References 150 publications

Deterioration of the human transcriptome with age due to increasing intron retention and spurious splicing

Deterioration of the human transcriptome with age due to increasing intron retention and spurious splicing

On How, and Why, and When, We Grow Old

Defining the age-dependent and tissue-specific circadian transcriptome in male mice

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