Which hallmarks of aging does epigenetic age reflect?

Multiple events occur as we age, leading to impaired functioning of our bodies and increased deterioration. To systematize these events, López-Otín et al. suggested nine main hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Another dimension crucial for understanding aging is time, as biological age frequently differs from simple chronological age.

To capture this temporal discrepancy, the researchers developed the epigenetic clocks – mathematical age estimators based on methylation occurring at specific positions in the genome. The difference between chronological age and epigenetic age is called epigenetic acceleration. Multiple epidemiological studies linked epigenetic acceleration to various pathologies, lifestyle traits, health and mental states, and environmental factors. But the question remains, what are the mechanisms behind the epigenetic clocks? How do the two spaces of epigenetic age and aging events relate? And are all of the hallmarks reflected in the epigenetic clock measurements?

‍

To answer these questions, Kabacik et al. set out on a quest to discover whether epigenetic aging manifests one or more aging hallmarks previously described. The researchers employed a multi-tissue Skin&blood epigenetic clock that outperforms most other epigenetic clocks in terms of accuracy and reliability. The experiments demonstrated that, in different primary human and mouse cells, epigenetic aging is not affected either by cellular senescence or by genomic instability caused by radiation-induced DNA breaks. On the other hand, findings show that nutrient sensing, mitochondrial function, stem cell exhaustion, and altered cell-cell communication significantly affect epigenetic aging as measured by the Skin&blood clock.

‍

The estimated connection of epigenetic aging to four hallmarks of aging points towards a connection between these hallmarks on a deeper level. If this hypothesis holds true, the epigenetic clocks may become an instrument for identifying the unifying mechanisms. The existence of an independent mechanism implies that aging results from parallel mechanisms that the authors suggest dividing into two groups: associated with epigenetic aging and those independent of it. Further, these hypotheses should be tested in animal experiments using universal mammalian epigenetic clocks.

‍

Source Nature Aging

‍