Flatt, T. A new definition of aging? Front. Genet. 3, 148 (2012).
Google Scholar
Berdasco, M. & Esteller, M. Hot topics in epigenetic mechanisms of aging: 2011. Aging Cell 11, 181–186 (2012).
Google Scholar
Jylhävä, J., Pedersen, N. L. & Hägg, S. Biological age predictors. EBioMedicine 21, 29–36 (2017).
Google Scholar
Wagner, K. H., Cameron-Smith, D., Wessner, B. & Franzke, B. Biomarkers of aging: from function to molecular biology. Nutrients 8, 338 (2016).
Field, A. E. et al. DNA methylation clocks in aging: categories, causes, and consequences. Mol. Cell 71, 882–895 (2018).
Google Scholar
Horvath, S. et al. Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring. Aging 7, 1159–1170 (2015).
Google Scholar
Nussey, D. H., Froy, H., Lemaitre, J. F., Gaillard, J. M. & Austad, S. N. Senescence in natural populations of animals: widespread evidence and its implications for bio-gerontology. Ageing Res. Rev. 12, 214–225 (2013).
Google Scholar
Johnson, T. E. Recent results: biomarkers of aging. Exp. Gerontol. 41, 1243–1246 (2006).
Google Scholar
Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, R115 (2013).
Google Scholar
Hannum, G. et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol. Cell 49, 359–367 (2013).
Google Scholar
Unnikrishnan, A. et al. The role of DNA methylation in epigenetics of aging. Pharmacol. Ther. 195, 172–185 (2019).
Google Scholar
Bocklandt, S. et al. Epigenetic predictor of age. PLoS ONE 6, e14821 (2011).
Google Scholar
Horvath, S. & Raj, K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat. Rev. Genet. 19, 371–384 (2018).
Google Scholar
Polanowski, A. M., Robbins, J., Chandler, D. & Jarman, S. N. Epigenetic estimation of age in humpback whales. Mol. Ecol. Resour. 14, 976–987 (2014).
Google Scholar
Petkovich, D. A. et al. Using DNA methylation profiling to evaluate biological age and longevity interventions. Cell Metab. 25, 954–960 (2017).
Google Scholar
Stubbs, T. M. et al. Multi-tissue DNA methylation age predictor in mouse. Genome Biol. 18, 68 (2017).
Google Scholar
Wang, T. et al. Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment. Genome Biol. 18, 57 (2017).
Google Scholar
Ito, G., Yoshimura, K. & Momoi, Y. Analysis of DNA methylation of potential age-related methylation sites in canine peripheral blood leukocytes. J. Vet. Med. Sci. 79, 745–750 (2017).
Google Scholar
Thompson, M. J., von Holdt, B., Horvath, S. & Pellegrini, M. An epigenetic aging clock for dogs and wolves. Aging 9, 1055–1068 (2017).
Google Scholar
Lowe, R. et al. Ageing-associated DNA methylation dynamics are a molecular readout of lifespan variation among mammalian species. Genome Biol. 19, 22 (2018).
Google Scholar
Zannas, A. S. et al. Lifetime stress accelerates epigenetic aging in an urban, African American cohort: relevance of glucocorticoid signaling. Genome Biol. 16, 266 (2015).
Google Scholar
Zaghlool, S. B. et al. Association of DNA methylation with age, gender, and smoking in an Arab population. Clin. Epigenetics 7, 6 (2015).
Google Scholar
Gao, X., Zhang, Y., Breitling, L. P. & Brenner, H. Relationship of tobacco smoking and smoking-related DNA methylation with epigenetic age acceleration. Oncotarget 7, 46878–46889 (2016).
Google Scholar
Marioni, R. E. et al. The epigenetic clock and telomere length are independently associated with chronological age and mortality. Int. J. Epidemiol. 45, 424–432 (2016).
Google Scholar
Marioni, R. E. et al. DNA methylation age of blood predicts all-cause mortality in later life. Genome Biol. 16, 25 (2015).
Google Scholar
Perna, L. et al. Epigenetic age acceleration predicts cancer, cardiovascular, and all-cause mortality in a German case cohort. Clin. Epigenetics 8, 64 (2016).
Google Scholar
Chen, B. H. et al. DNA methylation‐based measures of biological age: meta‐analysis predicting time to death. Aging 8, 1844–1859 (2016).
Google Scholar
Christiansen, L. et al. DNA methylation age is associated with mortality in a longitudinal Danish twin study. Aging Cell 15, 149–154 (2016).
Google Scholar
Horvath, S. & Levine, A. J. HIV-1 infection accelerates age according to the epigenetic clock. J. Infect. Dis. 212, 1563–1573 (2015).
Google Scholar
Horvath, S. et al. Accelerated epigenetic aging in Down syndrome. Aging Cell 14, 491–495 (2015).
Google Scholar
Parrott, B. B. & Bertucci, E. M. Epigenetic aging clocks in ecology and evolution. Trends Ecol. Evol. 34, 767–770 (2019).
Google Scholar
Wagner, W. Epigenetic aging clocks in mice and men. Genome Biol. 18, 107 (2017).
Google Scholar
Wang, T. et al. Quantitative translation of dog-to-human aging by conserved remodeling of the DNA methylome. Cell Syst. 11, 176–185 (2020).
Google Scholar
Wilkinson, G. S. & Adams, D. M. Recurrent evolution of extreme longevity in bats. Biol. Lett. 15, 20180860 (2019).
Google Scholar
Austad, S. N. Comparative biology of aging. J. Gerontol. A 64, 199–201 (2009).
Wu, C. W. & Storey, K. B. Life in the cold: links between mammalian hibernation and longevity. Biomol. Concepts 7, 41–52 (2016).
Google Scholar
Turbill, C., Bieber, C. & Ruf, T. Hibernation is associated with increased survival and the evolution of slow life histories among mammals. Proc. R. Soc. Lond. B 278, 3355–3363 (2011).
Chen, Y. et al. Mechanisms for increased levels of phosphorylation of elongation factor-2 during hibernation in ground squirrels. Biochemistry 40, 11565–11570 (2001).
Google Scholar
Knight, J. E. et al. mRNA stability and polysome loss in hibernating Arctic ground squirrels (Spermophilus parryii). Mol. Cell. Biol. 20, 6374–6379 (2000).
Google Scholar
Yan, J., Barnes, B. M., Kohl, F. & Marr, T. G. Modulation of gene expression in hibernating arctic ground squirrels. Physiol. Genomics 32, 170–181 (2008).
Google Scholar
Van Breukelen, F. & Martin, S. L. Molecular adaptations in mammalian hibernators: unique adaptations or generalized responses? J. Appl. Physiol. 92, 2640–2647 (2002).
Morin, P. & Storey, K. B. Evidence for a reduced transcriptional state during hibernation in ground squirrels. Cryobiology 53, 310–318 (2006).
Google Scholar
van Breukelen, F. & Martin, S. L. Reversible depression of transcription during hibernation. J. Comp. Physiol. B 172, 355–361 (2002).
Azzu, V. & Valencak, T. G. Energy metabolism and ageing in the mouse: a mini-review. Gerontology 63, 327–336 (2017).
Schrack, J. A., Knuth, N. D., Simonsick, E. M. & Ferrucci, L. ‘IDEAL’ aging is associated with lower resting metabolic rate: the Baltimore Longitudinal Study of Aging. J. Am. Geriatr. Soc. 62, 667–672 (2014).
Google Scholar
Al-attar, R. & Storey, K. B. Suspended in time: molecular responses to hibernation also promote longevity. Exp. Gerontol. 134, 110889 (2020).
Google Scholar
Carey, H. V., Andrews, M. T. & Martin, S. L. Mammalian hibernation: cellular and molecular responses to depressed metabolism and low temperature. Physiol. Rev. 83, 1153–1181 (2003).
Google Scholar
Turbill, C., Ruf, T., Smith, S. & Bieber, C. Seasonal variation in telomere length of a hibernating rodent. Biol. Lett. 9, 20121095 (2013).
Google Scholar
Turbill, C., Smith, S., Deimel, C. & Ruf, T. Daily torpor is associated with telomere length change over winter in Djungarian hamsters. Biol. Lett. 8, 304–307 (2012).
Google Scholar
Armitage, K. B., Blumstein, D. T. & Woods, B. C. Energetics of hibernating yellow-bellied marmots (Marmota flaviventris). Comp. Biochem. Physiol. A 134, 101–114 (2003).
Armitage, K. B. in Molecules to Migration: the Pressures of Life (eds Morris, S. & Vosloo, A.) 591–602 (Medimond Publishing, 2008).
Haghani, A. et al. DNA methylation networks underlying mammalian traits. Preprint at bioRxiv https://doi.org/10.1101/2021.03.16.435708 (2021).
Lu, A. T. et al. Universal DNA methylation age across mammalian tissues. Preprint at bioRxiv https://doi.org/10.1101/2021.01.18.426733 (2021).
Yang, S. et al. Rare mutations in AHDC1 in patients with obstructive sleep apnea. Biomed. Res. Int. https://doi.org/10.1155/2019/5907361 (2019).
De Paoli-Iseppi, R. et al. Measuring animal age with DNA methylation: from humans to wild animals. Front. Genet. 8, 106 (2017).
Google Scholar
Arneson, A. et al. A mammalian methylation array for profiling methylation levels at conserved sequences. Nat. Commun. 13, 783 (2022).
Google Scholar
Armitage, K. B. Reproductive strategies of yellow-bellied marmots: energy conservation and differences between the sexes. J. Mammal. 79, 385–393 (1998).
Armitage, K. B. in Adaptive Strategies and Diversity in Marmots (eds Ramousse, R. et al.) 133–142 (International Marmot Network, 2003).
Snir, S., Farrell, C. & Pellegrini, M. Human epigenetic ageing is logarithmic with time across the entire lifespan. Epigenetics 14, 912–926 (2019).
Google Scholar
Snir, S., VonHoldt, B. M. & Pellegrini, M. A statistical framework to identify deviation from time linearity in epigenetic aging. PLoS Comput. Biol. 12, e1005183 (2016).
Google Scholar
Farrell, C., Snir, S. & Pellegrini, M. The epigenetic pacemaker: modeling epigenetic states under an evolutionary framework. Bioinformatics 36, 4662–4663 (2020).
Google Scholar
Marioni, R. E. et al. Tracking the epigenetic clock across the human life course: a meta-analysis of longitudinal cohort data. J. Gerontol. A 74, 57–61 (2019).
El Khoury, L. Y. et al. Systematic underestimation of the epigenetic clock and age acceleration in older subjects. Genome Biol. 20, 283 (2019).
Google Scholar
Kilgore, D. L. & Armitage, K. B. Energetics of yellow-bellied marmot populations. Ecology 59, 78–88 (1978).
Armitage, K. B. Social and population dynamics of yellow-bellied marmots: results from long-term research. Annu. Rev. Ecol. Syst. 22, 379–407 (1991).
Webb, D. R. Environmental harshness, heat stress, and Marmota flaviventris. Oecologia 44, 390–395 (1980).
Armitage, K. B. Evolution of sociality in marmots. J. Mammal. 80, 1–10 (1999).
Allainé, D. Sociality, mating system and reproductive skew in marmots: evidence and hypotheses. Behav. Processes 51, 21–34 (2000).
Arnold, W. The evolution of marmot sociality. II. Costs and benefits of joint hibernation. Behav. Ecol. Sociobiol. 27, 239–246 (1990).
Villanueva-Cañas, J. L., Faherty, S. L., Yoder, A. D. & Albà, M. M. Comparative genomics of mammalian hibernators using gene networks. Integr. Comp. Biol. 54, 452–462 (2014).
Google Scholar
Lyman, C. P., O’Brien, R. C., Greene, G. C. & Papafrangos, E. D. Hibernation and longevity in the Turkish hamster Mesocricetus brandti. Science 212, 668–670 (1981).
Google Scholar
Kirby, R., Johnson, H. E., Alldredge, M. W. & Pauli, J. N. The cascading effects of human food on hibernation and cellular aging in free-ranging black bears. Sci. Rep. 9, 2197 (2019).
Google Scholar
Giroud, S. et al. Late-born intermittently fasted juvenile garden dormice use torpor to grow and fatten prior to hibernation: consequences for ageing processes. Proc. R. Soc. Lond. B 281, 20141131 (2014).
Hoelzl, F. et al. Telomeres are elongated in older individuals in a hibernating rodent, the edible dormouse (Glis glis). Sci. Rep. 6, 36856 (2016).
Google Scholar
Haussmann, M. F. & Mauck, R. A. Telomeres and longevity: testing an evolutionary hypothesis. Mol. Biol. Evol. 25, 220–228 (2008).
Google Scholar
van Lieshout, S. H. J. et al. Individual variation in early-life telomere length and survival in a wild mammal. Mol. Ecol. 28, 4152–4165 (2019).
Google Scholar
Lowe, D., Horvath, S. & Raj, K. Epigenetic clock analyses of cellular senescence and ageing. Oncotarget 7, 8524–8531 (2016).
Google Scholar
Kabacik, S., Horvath, S., Cohen, H. & Raj, K. Epigenetic ageing is distinct from senescence-mediated ageing and is not prevented by telomerase expression. Aging 10, 2800–2815 (2018).
Google Scholar
Keil, G., Cummings, E. & Magalhães, J. P. Being cool: how body temperature influences ageing and longevity. Biogerontology 16, 383–397 (2015).
Google Scholar
Means, L. W., Higgins, J. L. & Fernandez, T. J. Mid-life onset of dietary restriction extends life and prolongs cognitive functioning. Physiol. Behav. 54, 503–508 (1993).
Google Scholar
Speakman, J. R. & Mitchell, S. E. Caloric restriction. Mol. Aspects Med. 32, 159–221 (2011).
Google Scholar
Walford, R. L. & Spindler, S. R. The response to calorie restriction in mammals shows features also common to hibernation: a cross-adaptation hypothesis. J. Gerontol. A 52, B179–B183 (1997).
Google Scholar
Conti, B. et al. Transgenic mice with a reduced core body temperature have an increased life span. Science 314, 825–828 (2006).
Google Scholar
Conti, B. Considerations on temperature, longevity and aging. Cell. Mol. Life Sci. 65, 1626–1630 (2008).
Google Scholar
Gribble, K. E., Moran, B. M., Jones, S., Corey, E. L. & Mark Welch, D. B. Congeneric variability in lifespan extension and onset of senescence suggest active regulation of aging in response to low temperature. Exp. Gerontol. 114, 99–106 (2018).
Google Scholar
Johns, D. W. & Armitage, K. B. Behavioral ecology of alpine yellow-bellied marmots. Behav. Ecol. Sociobiol. 5, 133–157 (1979).
Armitage, K. B. Social behaviour of a colony of the yellow-bellied marmot (Marmota flaviventris). Anim. Behav. 10, 319–331 (1962).
Armitage, K. B. Vernal behaviour of the yellow-bellied marmot (Marmota flaviventris). Anim. Behav. 13, 59–68 (1965).
Armitage, K. B., Melcher, J. C. & Ward, J. M. Oxygen consumption and body temperature in yellow-bellied marmot populations from montane-mesic and lowland-xeric environments. J. Comp. Physiol. B 160, 491–502 (1990).
Sheriff, M. J., Williams, C. T., Kenagy, G. J., Buck, C. L. & Barnes, B. M. Thermoregulatory changes anticipate hibernation onset by 45 days: data from free-living arctic ground squirrels. J. Comp. Physiol. B 182, 841–847 (2012).
Google Scholar
Schwartz, C., Hampton, M. & Andrews, M. T. Hypothalamic gene expression underlying pre-hibernation satiety. Genes Brain Behav. 14, 310–318 (2015).
Google Scholar
Geiser, F. Metabolic rate and body temperature reduction during hibernation and daily torpor. Annu. Rev. Physiol. 66, 239–274 (2004).
Google Scholar
Maegawa, S. et al. Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res. 20, 332–340 (2010).
Google Scholar
Hampton, M., Melvin, R. G. & Andrews, M. T. Transcriptomic analysis of brown adipose tissue across the physiological extremes of natural hibernation. PLoS ONE 8, e85157 (2013).
Google Scholar
Lindner, M. et al. Temporal changes in DNA methylation and RNA expression in a small song bird: within- and between-tissue comparisons. BMC Genomics 22, 36 (2021).
Google Scholar
Schwartz, C., Hampton, M. & Andrews, M. T. Seasonal and regional differences in gene expression in the brain of a hibernating mammal. PLoS ONE 8, e58427 (2013).
Google Scholar
Dopico, X. C. et al. Widespread seasonal gene expression reveals annual differences in human immunity and physiology. Nat. Commun. 6, 7000 (2015).
Google Scholar
Jansen, H. T. et al. Hibernation induces widespread transcriptional remodeling in metabolic tissues of the grizzly bear. Commun. Biol. 2, 336 (2019).
Google Scholar
Viitaniemi, H. M. et al. Seasonal variation in genome-wide DNA methylation patterns and the onset of seasonal timing of reproduction in great tits. Genome Biol. Evol. 11, 970–983 (2019).
Google Scholar
Johnston, R. A., Paxton, K. L., Moore, F. R., Wayne, R. K. & Smith, T. B. Seasonal gene expression in a migratory songbird. Mol. Ecol. 25, 5680–5691 (2016).
Google Scholar
Boyer, B. B. & Barnes, B. M. Molecular and metabolic aspects of mammalian hibernation. Bioscience 49, 713–724 (1999).
Siutz, C., Ammann, V. & Millesi, E. Shallow torpor expression in free-ranging common hamsters with and without food supplements. Front. Ecol. Evol. 6, 190 (2018).
Langer, F., Havenstein, N. & Fietz, J. Flexibility is the key: metabolic and thermoregulatory behaviour in a small endotherm. J. Comp. Physiol. B 188, 553–563 (2018).
Google Scholar
Bieber, C., Turbill, C. & Ruf, T. Effects of aging on timing of hibernation and reproduction. Sci. Rep. 8, 13881 (2018).
Google Scholar
Storey, K. B. & Storey, J. M. Aestivation: signaling and hypometabolism. J. Exp. Biol. 215, 1425–1433 (2012).
Google Scholar
Krivoruchko, A. & Storey, K. B. Forever young: mechanisms of natural anoxia tolerance and potential links to longevity. Oxid. Med. Cell. Longev. 3, 186–198 (2010).
Google Scholar
Storey, K. B. & Storey, J. M. Metabolic rate depression in animals: transcriptional and translational controls. Biol. Rev. 79, 207–233 (2004).
Google Scholar
Puspitasari, A. et al. Hibernation as a tool for radiation protection in space exploration. Life 11, 54 (2021).
Google Scholar
Blumstein, D. T. Yellow-bellied marmots: insights from an emergent view of sociality. Philos. Trans. R. Soc. Lond. B 368, 20120349 (2013).
Armitage, K. B. & Downhower, J. F. Demography of yellow-bellied marmot populations. Ecology 55, 1233–1245 (1974).
Zhou, W., Triche, T. J., Laird, P. W. & Shen, H. SeSAMe: reducing artifactual detection of DNA methylation by Infinium BeadChips in genomic deletions. Nucleic Acids Res. 46, e123 (2018).
Google Scholar
Labarre, B. A. et al. MethylToSNP: identifying SNPs in Illumina DNA methylation array data. Epigenetics Chromatin 12, 79 (2019).
Google Scholar
Snir, S., Wolf, Y. I. & Koonin, E. V. Universal pacemaker of genome evolution. PLoS Comput. Biol. 8, e1002785 (2012).
Google Scholar
Zou, H. & Hastie, T. Regularization and variable selection via the elastic net. J. R. Stat. Soc. B 67, 301–320 (2005).
Friedman, J., Hastie, T. & Tibshirani, R. Regularization paths for generalized linear models via coordinate descent. J. Stat. Softw. 33, 1–22 (2010).
Google Scholar
Snir, S. & Pellegrini, M. An epigenetic pacemaker is detected via a fast conditional expectation maximization algorithm. Epigenomics 10, 695–706 (2018).
Google Scholar
Wood, S. & Scheipl, F. gamm4: Generalized additive mixed models using mgcv and lme4, R package version 0.2-3 (2014); http://cran.r-project.org/package=gamm4
R Core Team. R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, 2020).
RStudio Team. RStudio: Integrated Development Environment for R (RStudio Inc., 2019).
Van Rossum, G. & Drake, F. L. Python 3 Reference Manual (CreateSpace, 2009).
Kluyver, T. et al. in Positioning and Power in Academic Publishing: Players, Agents and Agendas (eds Loizides, F. & Scmidt, B.) 87–90 (IOS Press, 2016); https://doi.org/10.3233/978-1-61499-649-1-87
Wickham, H. ggplot2: Elegant Graphics for Data Analysis (Springer-Verlag, 2016).
Kassambara, A. ggpubr: ‘ggplot2’ based publication ready plots https://cran.r-project.org/package=ggpubr (2020).
Wood, S. N. Fast stable restricted maximum likelihood and marginal likelihood estimation of semiparametric generalized linear models. J. R. Stat. Soc. B 73, 3–36 (2011).
Kuznetsova, A., Brockhoff, P. B. & Christensen, R. H. B. lmerTest package: tests in linear mixed effects models. J. Stat. Softw. 82, 1–26 (2017).
Mclean, C. Y. et al. GREAT improves functional interpretation of cis-regulatory regions. Nat. Biotechnol. 28, 495–501 (2010).
Google Scholar
Pinho, G. M. et al. Hibernation slows epigenetic ageing in yellow-bellied marmots data sets. OSF https://doi.org/10.17605/OSF.IO/E42ZV (2021).
Source: Ecology - nature.com
