Abstract
Given the dramatic increase in ageing populations, it is of great importance to understand the genetic and molecular determinants of healthy ageing and longevity. Semi-supercentenarians (subjects who reached an age of 105-109 years) arguably represent the gold standard of successful human ageing because they managed to avoid or postpone the onset of major age-related diseases. Relatively few studies have looked at epigenetic determinants of extreme longevity in humans. Here we test whether families with extreme longevity are epigenetically distinct from controls according to an epigenetic biomarker of ageing which is known as "epigenetic clock". We analyze the DNA methylation levels of peripheral blood mononuclear cells (PBMCs) from Italian families constituted of 82 semi-supercentenarians (mean age: 105.6 ± 1.6 years), 63 semi-supercentenarians' offspring (mean age: 71.8 ± 7.8 years), and 47 age-matched controls (mean age: 69.8 ± 7.2 years). We demonstrate that the offspring of semi-supercentenarians have a lower epigenetic age than age-matched controls (age difference=5.1 years, p=0.00043) and that centenarians are younger (8.6 years) than expected based on their chronological age. By contrast, no significant difference could be observed for estimated blood cell counts (such as naïve or exhausted cytotoxic T cells or helper T cells). Future studies will be needed to replicate these findings in different populations and to extend them to other tissues. Overall, our results suggest that epigenetic processes might play a role in extreme longevity and healthy human ageing.
Highlights
Ageing researchers and the general public have long been intrigued by centenarians because these subjects managed to avoid, postpone or overcome the major agerelated diseases such as cancer [1], cardiovascular diseases [2], diabetes [3], osteoporotic fractures [4] and dementia [5, 6].We find it useful to further distinguish centenarians from semi-supercentenarians and supercentenarians because subjects in these latter categories are extremely rare
We find that peripheral blood mononuclear cells (PBMCs) of the offspring of 105+ age more slowly than that of age matched controls according to a) the Age Accel measure (Kruskal Wallis test p=0.012, Figure 1C) and b) the intrinsic measure of age acceleration (p=0.0016 Figure 1E)
To the best of our knowledge, this is the first study that demonstrates that the offspring of semi-supercentenarians have a lower intrinsic epigenetic ageing rate in PBMCs
Summary
Ageing researchers and the general public have long been intrigued by centenarians because these subjects managed to avoid, postpone or overcome the major agerelated diseases such as cancer [1], cardiovascular diseases [2], diabetes [3], osteoporotic fractures [4] and dementia [5, 6]. We find it useful to further distinguish centenarians from semi-supercentenarians (i.e. subjects that reach the age of 105 years, 105+) and supercentenarians (subjects that reach the age of 110 years, 110+) because subjects in these latter categories are extremely rare. The comparison of CO to age matched controls has already been successfully applied to identify biochemical and metabolomics parameters related to exceptional longevity [24, 26,27,28,29,30,31] and to define survival scores [32, 33]
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