Aging-related epigenetic changes

From Longevity Wiki

Epigenetics, a rapidly evolving field, refers to the study of modifications to gene expression that does not alter the DNA sequence. Epigenetic dysregulation is both a hallmark and a driver of aging and restoring epigenetic integrity can reverse aging phenotypes.[1]

Aging-related epigenetic changes, their impacts on gene expression, and the functional consequences thereof

(According to Wu et al., 2024[2])

Abbreviations: Aβ, amyloid β; APP, amyloid precursor protein; BACE1, beta-site APP cleaving enzyme 1; cGAS, cyclic GMP-AMP synthase; CYP1B1, cytochrome P450 family 1 subfamily B member 1; ERK, extracellular signal-regulated kinase; ERV, endogenous retrovirus; FASN, fatty acid synthase; IFN, interferon; LAD, lamina-associated domain; LINE-1, long-interspersed element-1; MAPK, mitogen-activated protein kinase; MMP13, matrix metalloproteinase 13; MSC, mesenchymal stem cell; OA, osteoarthritis; PSG, pregnancy-specific beta-1 glycoprotein; SASP, senescence-associated secretory phenotype; STING, stimulator of interferon genes.
Epigenetic change Gene expression Functional consequence Refs
Decreased DNA 5mC Upregulated CDKN2A (p16) Accelerated senescence of human cancer cells [3]
Upregulated APP and BACE1 Increased Aβ production in human neuroblastoma cells [4]
Decreased DNA 5mC and H3K9me3, increased H3K36me3 Upregulated endogenous retrovirus (ERV) Accelerated human MSC senescence [5]
Decreased DNA 5mC, H3K9me3 and H4K20me3, increased H3K27ac and H3K4me1 Upregulated PSG genes Accelerated human MSC senescence [6]
Decreased H3K9 and H3K36 methylation Upregulated SASP factors, p16, and CDKN1A (p21) Bleomycin-induced senescence of human prostate stromal cells [7]
Decreased H3K9me3 and H3K27me3 Upregulated LINE-1 Accelerated senescence of primary fibroblasts derived from patients with progeroid syndromes [8]
Decreased heterochromatin and LAD, increased chromatin accessibility Upregulated LINE-1 Accelerated human MSC senescence [9]
Decreased RNA m6A Downregulated MIS12 Accelerated human MSC senescence [10]
Downregulated NPNT Accelerated human myotube senescence [11]
Increased circRREB1 Upregulated FASN, MMP13, p16, p21, and TP53 (p53) Progression of chondrocyte senescence and OA pathogenesis in mice [12]
Increased DNA 5mC Downregulated ELOVL2 Aging of human fibroblasts [13]
Increased DNA 6mA Upregulated heat stress response genes Transgenerational longevity of Caenorhabditis elegans induced by heat shock [14]
Increased H3K14ac Upregulated CDKN2B (p15) Accelerated human MSC senescence [15]
Increased H3K27ac and H3K4me1 Upregulated HMGB2 Rejuvenation of senescent human MSCs and alleviation of OA in aged mice [16]
Increased H3K27ac and H3K9ac Upregulated Aβ Progression of AD-related degeneration [17]
Increased H3K4me3 Upregulated p21 Accelerated human MSC senescence [18]
Increased histone acetylation Upregulated p16 and p53 Accelerated senescence of human cancer cells [19]
Increased miR-145 Downregulated semaphorin-3A Alleviation of heart aging [20]
Increased miR-31 Repression of CLOCK and activation of MAPK/ERK signaling Accelerated skin aging [21]
Increased RNA m5C Repressed cGAS-STING activity Decreased IFN-β [22]
Increased RNA m6A Downregulated CDKN1C (p57) Alleviated MSC senescence, improved MSC survival and angiogenesis, and enhanced cardioprotective effect against myocardial infarction in mice [23]
Upregulated CYP1B1 Accelerated human MSC aging and onset of OA in mice [24]
Increased RNA m6A and m5C Upregulated p21 Oxidative stress-induced senescence of human cancer cells [25]

References

  1. ↑ Pereira, B., Correia, F. P., Alves, I. A., Costa, M., Gameiro, M., Martins, A. P., & Saraiva, J. A. (2024). Epigenetic Reprogramming as a Key to Reverse Ageing and Increase Longevity. Ageing Research Reviews, 102204. PMID: 38272265 DOI: 10.1016/j.arr.2024.102204
  2. ↑ Wu, Z., Zhang, W., Qu, J., & Liu, G. H. (2024). Emerging epigenetic insights into aging mechanisms and interventions. Trends in Pharmacological Sciences. PMID: 38216430 DOI: 10.1016/j.tips.2023.12.002
  3. ↑ Wang L. et al. Exploiting senescence for the treatment of cancer. Nat. Rev. Cancer. 2022; 22: 340-355
  4. ↑ Wu Z. et al. Stress, epigenetics, and aging: unraveling the intricate crosstalk. Mol. Cell. 2023; 84: 34-54
  5. ↑ Liu X. et al. Resurrection of endogenous retroviruses during aging reinforces senescence. Cell. 2023; 186: 287-304
  6. ↑ Liu Z. et al. Large-scale chromatin reorganization reactivates placenta-specific genes that drive cellular aging. Dev. Cell. 2022; 57: 1347-1368
  7. ↑ Zhang B. et al. KDM4 orchestrates epigenomic remodeling of senescent cells and potentiates the senescence-associated secretory phenotype. Nat. Aging. 2021; 1: 454-472
  8. ↑ Della Valle F. et al. LINE-1 RNA causes heterochromatin erosion and is a target for amelioration of senescent phenotypes in progeroid syndromes. Sci. Transl. Med. 2022; 14eabl6057
  9. ↑ Bi S. et al. SIRT7 antagonizes human stem cell aging as a heterochromatin stabilizer. Protein Cell. 2020; 11: 483-504
  10. ↑ Wu Z. et al. METTL3 counteracts premature aging via m6A-dependent stabilization of MIS12 mRNA. Nucleic Acids Res. 2020; 48: 11083-11096
  11. ↑ Wu Z. et al. m6A epitranscriptomic regulation of tissue homeostasis during primate aging. Nat. Aging. 2023; 3: 705-721
  12. ↑ Gong Z. et al. CircRREB1 mediates lipid metabolism related senescent phenotypes in chondrocytes through FASN post-translational modifications. Nat. Commun. 2023; 14: 5242
  13. ↑ Li X. et al. Lipid metabolism dysfunction induced by age-dependent DNA methylation accelerates aging. Signal Transduct. Target. Ther. 2022; 7: 162
  14. ↑ Wan Q.L. et al. N(6)-methyldeoxyadenine and histone methylation mediate transgenerational survival advantages induced by hormetic heat stress. Sci. Adv. 2021; 7eabc3026
  15. ↑ Wang W. et al. A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence. Sci. Transl. Med. 2021; 13eabd2655
  16. ↑ Jing Y. et al. Genome-wide CRISPR activation screening in senescent cells reveals SOX5 as a driver and therapeutic target of rejuvenation. Cell Stem Cell. 2023; 30: 1452-1471
  17. ↑ Nativio R. et al.An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer's disease. Nat. Genet. 2020; 52: 1024-1035
  18. ↑ Yan K. et al. SGF29 nuclear condensates reinforce cellular aging. Cell Discov. 2023; 9: 110
  19. ↑ Wang L. et al. Exploiting senescence for the treatment of cancer. Nat. Rev. Cancer. 2022; 22: 340-355
  20. ↑ Wagner J.U.G.et al.Aging impairs the neurovascular interface in the heart. Science. 2023; 381: 897-906
  21. ↑ Yu Y.et al. A stress-induced miR-31-CLOCK-ERK pathway is a key driver and therapeutic target for skin aging. Nat. Aging. 2021; 1: 795-809
  22. ↑ Chen T. et al. NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance. Cell Metab. 2023; 35: 1782-1798
  23. ↑ Gao X. et al. Downregulation of ALKBH5 rejuvenates aged human mesenchymal stem cells and enhances their therapeutic efficacy in myocardial infarction. FASEB J. 2023; 37e23294
  24. ↑ Ye G.et al. ALKBH5 facilitates CYP1B1 mRNA degradation via m6A demethylation to alleviate MSC senescence and osteoarthritis progression. Exp. Mol. Med. 2023; 55: 1743-1756
  25. ↑ Li Q. et al. NSUN2-mediated m5C methylation and METTL3/METTL14-mediated m6A methylation cooperatively enhance p21 translation. J. Cell. Biochem. 2017; 118: 2587-2598
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