Deconvolution of the epigenetic age discloses distinct inter-personal variability in epigenetic aging patterns

Abstract

Background The epigenetic age can now be extrapolated from one of several epigenetic clocks, which are based on age-related changes in DNA methylation levels at specific multiple CpG sites. Accelerated aging, calculated from the discrepancy between the chronological age and the epigenetic age, has shown to predict morbidity and mortality rate. We assumed that deconvolution of epigenetic age to its components could shed light on the diversity of epigenetic, and by inference, on inter-individual variability in the causes of biological aging. Results Using the Horvath original epigenetic clock, we identified several CpG sites linked to distinct genes that quantitatively explain much of the inter-personal variability in epigenetic aging, with CpG sites related to secretagogin and malin being the most variable. We show that equal epigenetic age in different subjects can result from variable contribution size of the same CpG sites to the total epigenetic age. In a healthy cohort, the most variable CpG sites are responsible for accelerated and decelerated epigenetic aging, relative to chronological age. Conclusions Of the 353 CpG sites that form the basis for the Horvath epigenetic age, we have found the CpG sites that are responsible for accelerated and decelerated epigenetic aging in healthy subjects. However, the relative contribution of each site to aging varies between individuals, leading to variable personal aging patterns. Our findings pave the way to form personalized aging cards allowing the identification of specific genes related to CpG sites, as aging markers, and perhaps treatment of these targets in order to hinder undesirable age drifting.

Epigenetic aging waves: Artificial intelligence detects clustering of switch points in DNA methylation rate in defined sex-dependent age periods

“…At the present phase, the conceptualization of the ESPs waves as a potentially significant phenomenon, requires consideration of the fact that whereas aging itself, including epigenetic aging (5)(6)(7)14) goes on continuously with advancing years, the ESPs waves apparently begin to wane after the age of ~58 in men and ~63 in women and then completely disappear within In conclusion, this is the first report of epigenetic aging waves in the form of clustering of EPS in a fraction of the genes comprising the human genome, in an age and sex specific manner. The main weakness of this report is that it is based on cross sectional analysis of mean methylation level and not on longitudinal observations in the same individuals and therefore does not deal with intra-individual changes in DNA methylation.…”

“…That certain CpG sites are closely and linearly related to age has been utilized by Horvath et al (4,5), Hannum (11), and Weidner et al (12) to formulate the concept of age/time related epigenetic clocks, according to which an epigenetic age, in years, can be mathematically derived from specific CpG sites such that it approximately parallels the chronological age. Shahal et al (14) subsequently deconvoluted the Horvath's epigenetic clock to its components, showing significant interindividual variability. Furthermore, a large body of work now links upward drifting from the epigenetic age, which reflects accelerated epigenetic aging, to earlier mortality, decreased healthy longevity and a number of diseases, such as breast cancer (15)(16)(17)(18)(19)(20)(21).…”

“…evolution and the epigenetic waves and their individual components comprises a formidable challenge for future work .At the present phase, the conceptualization of the ESPs waves as a potentially significant phenomenon, requires consideration of the fact that whereas aging itself, including epigenetic aging(5)(6)(7)14) goes on continuously with advancing years, the ESPs waves apparently begin to wane after the age of ~58 in men and ~63 in women and then completely disappear within the following 5-8 years. This transient pattern of epigenetic waves might indicate that the CpG signals comprising the ESP waves are mechanistically involved in or at the least echo some biological resetting that permits aging to advance, but may also reflect compensatory prolongevity biosystems activated by signals of aging and senescence.…”

Assessing brain and biological aging trajectories associated with Alzheimer’s disease

“…The absence of correlations may also arise from capturing distinct aging processes. Inter-individual variability in methylation profiles, based on the Horvath clock, has been observed in those with the same chronological age and different epigenetic age, as well as for those with the same chronologic and epigenetic age ( Shahal et al, 2022 ). In middle-aged adults, Horvath’s clock also demonstrated variability within separate memory performance groups, with a lower epigenetic age observed in subjects who sustained memory functions over time ( Degerman et al, 2017 ).…”

Homocysteine exchange across skeletal muscle in patients with chronic kidney disease

“…The renewed interest in Hcy as a player in the methylation processes in aging and cachexia (Bauchart-Thevret et al, 2009;Ducker & Rabinowitz, 2017;Shahal et al, 2022; F I G U R E 1 Pathways of methionine metabolism in skeletal muscle. Methionine synthase (MS) is expressed, although at intermediate level, in skeletal muscle.…”