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Universal epigenetic clocks provide insights into why mammals are ‘born to die’

A humpback whale flukes its tail out of the water as it prepares to dive

Gareth Jones

A humpback whale breaching the surface of the water with its face

Gareth Jones

A close-up of a mouse coming down a tree vertically.

Gareth Jones

Press release issued: 7 November 2023

Benjamin Franklin famously stated ‘in this world nothing can be said to be certain, except death and taxes’. But why are we ‘born to die’ and what mechanisms underpin the gradual decline in biological functions (senescence) in living organisms, and ultimately their death? We are at an exciting point in ageing research: a Universal Mammalian Clock Chip has been developed using data on DNA methylation (DNAm) from a wide range of mammals and tissue types to predict the chronological age of any mammal species accurately from a single equation, also showing how DNAm changes in predictable ways over an animal’s life. Two new papers1,2 provide remarkable insights into ageing. The findings reveal great potential for estimating a mammal’s chronological age when it is not known, for understanding why some individuals age faster than expected for their chronological age, and for understanding factors affecting the large variation in the lifespans of different mammal species.

DNAm is an ‘epigenetic’ process in which methyl groups are added to DNA, potentially modifying gene functions such as gene expression that can affect phenotypes. DNAm-based biomarkers known as ‘epigenetic clocks’ provide accurate estimates of chronological age in healthy humans and vertebrates and the clocks tick faster during chronic disease, frailty and under adverse exposures. We all know people who look old and young even though they are the same chronological age, and differences in DNAm may partly explain how they have different ‘biological ages’. Indeed, most research on DNAm had previously focused on humans who often experience health interventions and are hence differ radically from wild mammals where natural selection is more intense. Work on DNAm in wild mammal populations has accelerated in recent years, and two papers published simultaneously today in Nature Aging1 and Science2 describe a universal mammal clock and identify parts of the genome where methylation relates to age within species, and to differences in lifespan across species. 

The mammalian methylation clock allows prediction of chronological age from changes in DNAm at only tens of thousands of sites in the genome. An international team of scientists in the Mammalian Methylation Consortium, including Gareth Jones from the School of Biological Sciences collaborated on the papers which were led by Steve Horvath, Amin Haghani, Caesar Li and Ake Lu from UCLA and Altos Labs. One analysis looked at DNAm from 59 tissues taken from 185 mammal species with samples ranging in age from pre-birth to a bowhead whale aged 139 years.  Tissue age could be predicted with high accuracy across all mammal species studied from DNAm. Moreover, faster ticking universal clocks were associated with increased mortality risk in humans, and slower ticking occurred during caloric restriction in mice. Specific cytosine sites showed consistent age-related changes in DNAm across species, showing that methylation patterns are conserved over evolution. These sites were close to genes implicated in development, cancer, obesity and longevity. 

Evolutionary trees show branching patterns illustrating how organisms diverged from shared ancestors. Trees built from epigenetic data showed similar branching patterns to established trees developed from gene sequences. Methylation signatures associated with maximum life span across mammal species that were independent of age showed for example that long-lived species evolved methylation states at HOX genes associated with developmental processes, probably affected by pluripotency transcription factors that regulate reprogramming of body cells into multiple other cell types. 

The findings show that changes in DNAm are the consequence of consistent evolutionary processes across mammal species and reject the hypothesis that ageing is the consequence of random accumulation of cellular damage. The universal mammal clock will be useful in studies for ageing wild mammals from DNA samples, and potentially for understanding which areas of the genome could be targets for anti-ageing interventions in humans. DNAm also gives insights into understanding why animals age by identifying mechanisms underpinning ageing and ultimately death. Evolutionary theories propose that death may be ‘programmed’ according to features such as reproductive output and lifespan. Ultimately, from a ‘selfish gene’ perspective, death allows genes the ability to reshuffle with other genes, perhaps to generate new variants that can combat emerging pathogens better and ensure the genes’ survival in the long-term. The new studies provide insights into how, and potentially why, mammals - including ourselves- are ‘born to die’.

Further information

  1. Lu, AT et al. (2023). Universal DNA methylation age across mammalian tissues. Nature Aging.
  2. Haghani, A et al. (2023). DNA methylation networks underlying mammalian traits. Science 381: eabq5693

Figure: The maximum life span of mammals varies between about one to over 200 years. Towards these extremes, the wood mouse illustrated may live for at most a year in the wild, the humpback whale 95 years.  New research on DNA methylation provides some explanations for how this variation evolved. 

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