Death Becomes Her, or Why Aging is an Epigenetic Program

Evidence in support of the Strong Epigenetic Theory of Aging

Epigenetic clocks accurately show your expected remaining lifespan. Sort of like in that In Time movie.

The Great Gladyshev Group Paper

Not Entropy Again

(с) Shannon entropy of the sites that significantly change (or do not change) with age.
(D) Shannon entropy of the sites that significantly increase and decrease with age.
Age-related changes in entropy of the human DNA methylome.
(A) Shannon entropy of the sites that significantly change (or do not change) with age in 651 human samples from the age of 19 to 101 years. Permutation test was performed to assess the difference in entropy between changing and non-changing groups.
(B) Shannon entropy of the sites that significantly increase and decrease with age in 651 human samples from the age of 19 to 101 years. Permutation test was performed to assess the difference in entropy for increasing and decreasing groups.
Age-related increases in entropy of the DNA methylome.
(A) Shannon entropy of 141 C57BL/6 mouse samples, calculated for every site.
(B) Shannon entropy of the same samples, calculated only for the sites that significantly change with age.

Methylation with Age

(a) Age-related changes in DNA methylation, shown as a density plot accounting for all detected CpG sites.
(b) Same as in (a), but the plots include only the CpG sites that significantly change with age.
Age-related changes in DNA methylation of genes. Relative position was calculated for every gene (0 corresponds to the TSS and 1 to the end of the gene) and extended in both directions up to the length of the gene. Dotted lines (individual samples) and thick lines (age groups) were calculated by generalized additive model using significant sites.
Age-related changes in DNA methylation of certain genomic elements.
(A) Age-related changes in methylation of long non-coding RNAs. Relative positions are shown as 0 (where the element begins) and 1 (where the element ends) and extended upstream (-1) and downstream (2) according to the length of the genomic region. Lines were calculated by generalized additive model based on the significantly changed sites. Color scheme shows the age, dotted lines show individual samples, and thick lines show age groups.
Age-related changes in methylation of repetitive elements in the genome.
Regression slope of linear regression for every genomic region, including only the significant sites, based on the RefFreeEWAS analysis.

What happens to the sites in methylation clocks?

Chronological age (y-axis) versus DNAm age (x-axis) in the test data. (A) Across all test data, the age correlation is 0.96 and the error is 3.6 years. Results for (B) CD4 T cells measured at birth (age zero) and at age 1 (cor = 0.78, error = 0.27 years), (С) CD4 T cells and CD14 monocytes (cor = 0.90, error = 3.7), (D) peripheral blood mononuclear cells (cor = 0.96, error = 1.9), (E) whole blood (cor = 0.95, error = 3.7), (F) cerebellar samples (cor = 0.92, error = 5.9), (G) occipital cortex (cor = 0.98, error = 1.5), (H) normal adjacent breast tissue (cor = 0.87, error = 13), (I) buccal epithelium (cor = 0.83, error = 0.37), (J) colon (cor = 0.85, error = 5.6), (K) fat adipose (cor = 0.65, error = 2.7), (L) heart (cor = 0.77, error = 12), (M) kidney (cor = 0.86, error = 4.6), (N) liver (cor = 0.89, error = 6.7), (O) lung (cor = 0.87, error = 5.2), (P) muscle (cor = 0.70, error = 18), (Q) saliva (cor = 0.83, error = 2.7), ® uterine cervix (cor = 0.75, error = 6.2), (S) uterine endometrium (cor = 0.55, 11), (T) various blood samples composed of 10 Epstein Barr Virus transformed B cell, three naive B cell, and three peripheral blood mononuclear cell samples (cor = 0.46, error = 4.4). Samples are colored by disease status: brown for Werner progeroid syndrome, blue for Hutchinson-Gilford progeria, and turquoise for healthy control subjects.

What genes in methylation clocks change the most with age?

Not all clocks are created equal

Turning off “good” genes with age

Not by methylation alone

Targeting of DNA methylation and H3K9 methylation to (a) heterochromatin, where it interacts with the H3K9 methylation system, and (b) gene bodies, where it may interact with H3K36 methylation to target DNA methylation to these regions. Several alternative but not mutually exclusive models are shown here.

Could Alzheimer’s also be epigenetically controlled?

FAD mice exhibited deficits in novel object recognition memory, working memory and spatial memory, which was rescued by EHMT1/2 inhibitors.
(A) Bar graphs (mean ± SEM) showing the discrimination ratio of novel object recognition (NOR) tests in wild-type (WT) versus FAD mice (5–6 months old) without or with the treatment of BIX01294 (1 mg/kg, s.c. 3x) or UNC0642 (1 mg/kg, i.p. 3x). **P < 0.01, one-way ANOVA. (B) Representative heat maps illustrating the time spent in different locations of the arena for novel object recognition tests of all groups (blue: 0 s; red: ~10 s). Locations of novel (denoted by an arrow) and familiar objects are labelled with the circles or squares. (С) Scatter plots showing the discrimination ratio of novel object recognition tests in each of the examined wild-type or FAD mice before and after the treatment with BIX01294 or UNC0642. *P < 0.05, ***P < 0.001, paired t-test. (D) Bar graphs (mean ± SEM) showing the percentage correctness in T-maze working memory (WM) tests in wild-type or FAD mice with or without BIX01294 treatment. *P < 0.05, **P < 0.01, two-way ANOVA. (E) Scatter plots showing the percentage correctness in T-maze tests in each of the examined FAD mice before and after BIX01294 treatment. ***P < 0.001, paired t-test. (F) Representative heat maps illustrating the time spent in different locations of the arena for Barnes maze tests during the memory phase (escape box removed) in wild-type versus FAD mice without or with the treatment of BIX01294 (1 mg/kg, s.c. 3x) or UNC0642 (1 mg/kg, i.p. 3x) (blue: 0 s; red: ~10 s). Locations of the correct (indicated by an arrow) and seven incorrect holes are labelled with circles. (G) Bar graphs (mean +/ SEM) showing the time spent on exploring the correct hole (T1) versus the seven incorrect holes (T2) in the memory phase of Barnes maze tests of all groups. *P < 0.05, **P < 0.01, ***P < 0.001, two-way ANOVA. (H) Bar graphs (mean +/ SEM) showing the spatial memory index (T1/T2) of Barnes maze tests in wild-type versus FAD mice without or with the treatment of BIX01294 or UNC0642. ***P < 0.001, two-way ANOVA. (I) Scatter plots showing the spatial memory index in Barnes maze tests in each of the examined FAD mice before and after the treatment with BIX01294 or UNC0642. **P < 0.01, ***P < 0.001, paired t-test. (J) Plots (mean +/ SEM) of spatial memory index in FAD mice treated with BIX01294 (1 mg/kg, s.c. 3x) or saline at different time points. **P < 0.01, ***P < 0.001, saline versus BIX01294; ##P < 0.01, ###P < 0.001, pre- versus post-injection, two-way ANOVA. Each set of the experiments was replicated between four and five times.

Epigenetic rollback (rejuvenation)

Could epigenetic clocks just be a reflection of DNA damage?

References and Further Reading

  1. Mitteldorf, J, 2016, An Epigenetic Clock Controls Aging, Biogerontology, 17:257–265
  2. Mitteldorf, J, 2017, Aging is a Group-Selected Adaptation. Theory, Evidence, and Medical Implications
  3. Adiv Johnson et al, Rejuv Res 2012, The Role of DNA Methylation in Aging, Rejuvenation, and Age-Related Disease
  4. Rando & Chang, Cell 2012, Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock
  5. Horvath, S, and K. Raj, 2018, DNA Methylation-based Biomarkers and the Epigenetic Clock Theory of Ageing, Nature Reviews, 19:371–384
  6. Galkin, F, 2020, Biohorology and biomarkers of aging: Current state-of-the-art, challenges and opportunities, Aging Research Reviews 60:1–13

--

--

Preventing death is my life’s mission. I am a drug developer currently working on a rejuvenating gene therapy using the approach of partial reprogramming.

Get the Medium app

A button that says 'Download on the App Store', and if clicked it will lead you to the iOS App store
A button that says 'Get it on, Google Play', and if clicked it will lead you to the Google Play store
Yuri Deigin

Preventing death is my life’s mission. I am a drug developer currently working on a rejuvenating gene therapy using the approach of partial reprogramming.