Somatic mutation rates scale with lifespan across mammals

Cagan, Alexander; Baez‐Ortega, Adrian; Brzozowska, Natalia; Abascal, Federico; Coorens, Tim; Sanders, Mathijs A.; Lawson, Andrew; Harvey, Luke M. R.; Bhosle, Shriram G.; Jones, David R.; Alcantara, Raul E.; Butler, Timothy; Hooks, Yvette; Roberts, Kirsty; Anderson, Elizabeth; Lunn, Sharna; Flach, Edmund; Spiro, Simon; Januszczak, Inez; Wrigglesworth, Ethan; Jenkins, Hannah; Dallas, Tilly; Masters, Nic; Perkins, Matthew; Deaville, Robert; Druce, Megan; Bogeska, Ruzhica; Milsom, Michael D.; Neumann, Björn; Gorman, Frank; Constantino‐Casas, Fernando; Peachey, Laura; Bochyńska, Diana; Smith, Ewan St. John; Gerstung, Moritz; Campbell, Peter J.; Murchison, Elizabeth P.; Stratton, Michael R.; Martincorena, Iñigo

doi:10.1038/s41586-022-04618-z

Cited by 271 publications

(262 citation statements)

References 71 publications

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“…Some authors consider transcriptional noise to be a hallmark of aging in and of itself ( Mendenhall et al, 2021 ). Since aging is multifactorial and mutational load most likely leads to clonal expansion of aberrant cells that accumulate throughout the lifetime of the individual, other authors suggest that aging traits may be associated with cell type imbalance in aged organs ( Cagan et al, 2022 ). Another recent hypothesis is inter-tissue convergence through age-associated loss of specialization ( Izgi et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Lack of evidence for increased transcriptional noise in aged tissues

Ibáñez-Solé

Ascensión

Araúzo-Bravo

et al. 2022

Preprint

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Aging is often associated with a loss of cell type identity that results in an increase in transcriptional noise in aged tissues. If this phenomenon reflects a fundamental property of aging remains an open question. Transcriptional changes at the cellular level are best detected by single-cell RNA sequencing (scRNAseq). However, the diverse computational methods used for the quantification of age-related loss of cellular identity have prevented reaching meaningful conclusions by direct comparison of existing scRNAseq datasets. To address these issues we created Decibel, a Python toolkit that implements side-to-side four commonly used methods for the quantification of age-related transcriptional noise in scRNAseq data. Additionally, we developed Scallop, a novel computational method for the quantification of membership of single cells to their assigned cell type cluster. Cells with a greater Scallop membership score are transcriptionally more stable. Application of these computational tools to seven aging datasets showed large variability between tissues and datasets, suggesting that increased transcriptional noise is not a universal hallmark of aging. To understand the source of apparent loss of cell type identity associated with aging, we analyzed cell type-specific changes in transcriptional noise and the changes in cell type composition of the mammalian lung. No robust pattern of cell type-specific transcriptional noise alteration was found across aging lung datasets. In contrast, age-associated changes in cell type composition of the lung were consistently found, particularly of immune cells. These results suggest that claims of increased transcriptional noise of aged tissues should be reformulated.

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Section: Discussionmentioning

confidence: 99%

Lack of evidence for increased transcriptional noise in aged tissues

Ibáñez-Solé

Ascensión

Araúzo-Bravo

et al. 2022

Preprint

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“…The somatic mutation rate per year varied greatly across species and showed a strong inverse relationship with species lifespan. Therefore, the most remarkable datum of this study is the inverse scaling of somatic mutation rates with lifespan, suggesting that mutation rates may be a contributing factor in aging and longevity [ 76 ].…”

Section: Genes Shown To Be Associated With Longevitymentioning

confidence: 99%

How Important Are Genes to Achieve Longevity?

Caruso

Ligotti

Accardi

et al. 2022

IJMS

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Several studies on the genetics of longevity have been reviewed in this paper. The results show that, despite efforts and new technologies, only two genes, APOE and FOXO3A, involved in the protection of cardiovascular diseases, have been shown to be associated with longevity in nearly all studies. This happens because the genetic determinants of longevity are dynamic and depend on the environmental history of a given population. In fact, population-specific genes are thought to play a greater role in the attainment of longevity than those shared between different populations. Hence, it is not surprising that GWAS replicated associations of common variants with longevity have been few, if any, as these studies pool together different populations. An alternative way might be the study of long-life families. This type of approach is proving to be an ideal resource for uncovering protective alleles and associated biological signatures for healthy aging phenotypes and exceptional longevity.

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“…About 18% of protein molecules in the cell harbor at least one missense mutation due to errors in translation [ 70 ]. In addition, proteins incur mutations due to germline and somatic gene polymorphism [ 71 ]. Given that about 30–40% of random substitutions disrupt protein functions [ 72 , 73 ], most probably by loss-of-folding [ 74 , 75 ], it is likely that many cellular protein molecules have compromised thermal stability and the native structures of some will not be the free energy minima.…”

Section: Resultsmentioning

confidence: 99%

Non-Equilibrium Protein Folding and Activation by ATP-Driven Chaperones

2022

Biomolecules

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Recent experimental studies suggest that ATP-driven molecular chaperones can stabilize protein substrates in their native structures out of thermal equilibrium. The mechanism of such non-equilibrium protein folding is an open question. Based on available structural and biochemical evidence, I propose here a unifying principle that underlies the conversion of chemical energy from ATP hydrolysis to the conformational free energy associated with protein folding and activation. I demonstrate that non-equilibrium folding requires the chaperones to break at least one of four symmetry conditions. The Hsp70 and Hsp90 chaperones each break a different subset of these symmetries and thus they use different mechanisms for non-equilibrium protein folding. I derive an upper bound on the non-equilibrium elevation of the native concentration, which implies that non-equilibrium folding only occurs in slow-folding proteins that adopt an unstable intermediate conformation in binding to ATP-driven chaperones. Contrary to the long-held view of Anfinsen’s hypothesis that proteins fold to their conformational free energy minima, my results predict that some proteins may fold into thermodynamically unstable native structures with the assistance of ATP-driven chaperones, and that the native structures of some chaperone-dependent proteins may be shaped by their chaperone-mediated folding pathways.

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Somatic mutation rates scale with lifespan across mammals

Cited by 271 publications

References 71 publications

Lack of evidence for increased transcriptional noise in aged tissues

Lack of evidence for increased transcriptional noise in aged tissues

How Important Are Genes to Achieve Longevity?

Non-Equilibrium Protein Folding and Activation by ATP-Driven Chaperones

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