Aging is often perceived as a degenerative process caused by random accrual of cellular damage over time. In spite of this, age can be accurately estimated by epigenetic clocks based on DNA methylation profiles from almost any tissue of the body. Since such pan-tissue epigenetic clocks have been successfully developed for several different species, it is difficult to ignore the likelihood that a defined and shared mechanism instead, underlies the aging process. To address this, we generated 10,000 methylation arrays, each profiling up to 37,000 cytosines in highly-conserved stretches of DNA, from over 59 tissue-types derived from 128 mammalian species. From these, we identified and characterized specific cytosines, whose methylation levels change with age across mammalian species. Genes associated with these cytosines are greatly enriched in mammalian developmental processes and implicated in age-associated diseases. From the methylation profiles of these age-related cytosines, we successfully constructed three highly accurate universal mammalian clocks for eutherians, and one universal clock for marsupials. The universal clocks for eutherians are similarly accurate for estimating ages (r>0.96) of any mammalian species and tissue with a single mathematical formula. Collectively, these new observations support the notion that aging is indeed evolutionarily conserved and coupled to developmental processes across all mammalian species - a notion that was long-debated without the benefit of this new and compelling evidence.

The notion that the germ line does not age goes back to the 19th-century ideas of August Weismann. However, being metabolically active, the germ line accumulates damage and other changes over time, i.e., it ages. For new life to begin in the same young state, the germ line must be rejuvenated in the offspring. Here, we developed a multi-tissue epigenetic clock and applied it, together with other aging clocks, to track changes in biological age during mouse and human prenatal development. This analysis revealed a significant decrease in biological age, i.e., rejuvenation, during early stages of embryogenesis, followed by an increase in later stages. We further found that pluripotent stem cells do not age even after extensive passaging and that the examined epigenetic age dynamics is conserved across species. Overall, this study uncovers a natural rejuvenation event during embryogenesis and suggests that the minimal biological age (ground zero) marks the beginning of organismal aging.

Our society faces unprecedented challenges as the global pandemic of the coronavirus disease 2019 (COVID-19) spreads around the world, with more than 12.5 million cases and 550,000 deaths reported ("WHO", 2020). The disease is caused by an enveloped single-stranded positive RNA virus named severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 (Wu, Zhao, et al., 2020). In contrast to other coronaviruses, SARS-CoV-2 has the ability to infiltrate the lower respiratory tract resulting in severe lung damage and a high rate of deaths from pneumonia (Zhu et al., 2020). Older subjects, men, and those with pre-existing conditions such as hypertension, diabetes, cancer, heart failure, and chronic obstructive pulmonary disease are more prevalent among hospitalized COVID-19 patients (Richardson et al., 2020; Wang et al., 2020). Clinical risk factors for COVID-19-related deaths have been identified using a very large cohort (Williamson et al., 2020). The most common comorbidities have age as a risk factor and have been described in recent years as age-related diseases. The COVID-19 case fatality rate (CFR), that is, the quotient of deaths to confirmed infections, was shown to be lower in patients below 60 years old (1.4% [0.4-3.5]) compared to those who were 60 years or older (4.5%