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]

Six drivers of aging identified among genes differentially expressed with age

(According to preliminary results of Ariella Coler-Reilly, Zachary Pincus, Erica L Scheller and Roberto Civitell.[26] available under a CC-BY-NC 4.0 International license.

Therapeutic directions cannot be extrapolated from purely observational gene expression data, where drivers of aging cannot be distinguished from compensatory protective responses and irrelevant downstream effects.

The top age-upregulated genes were TMEM176A, EFEMP1, CP, and HLA-A;

the top age-downregulated genes were CA4, SIAH, SPARC, and UQCR10.

  • EFEMP1, also known as fibulin-3, is an extracellular matrix glycoprotein strongly associated with aging pathologies: overexpression contributes to age-related macular degeneration, high plasma levels are associated with signs of brain aging and higher risk of dementia, and upregulation of this gene is associated with Werner syndrome, a premature aging

condition.

  • CP, or ceruloplasmin, is a copper-binding glycoprotein involved in iron metabolism and defense against oxidative stress; decreased CP activity is associated with advanced age and age-related diseases, such as Parkinson’s and Alzheimer’s disease


Out of 10 age-upregulated and 9 age-downregulated genes that were tested, six genes were with evolutionarily conserved, causal roles in the aging process:

two age-upregulated genes (csp-3/CASP1 and spch-2/RSRC1) and

four age-downregulated genes (C42C1.8/DIRC2, ost-1/SPARC, fzy-1/CDC20, and cah-3/CA4) produced significant and reproducible lifespan extension when knocked down in C. elegans.

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
  26. ↑ Ariella Coler-Reilly, Zachary Pincus, Erica L Scheller, Roberto Civitelli (2024). Six drivers of aging identified among genes differentially expressed with age. bioRxiv 2024.08.02.606402; doi: https://doi.org/10.1101/2024.08.02.606402
Retrieved from ‘https://en.longevitywiki.org/index.php?title=Aging-related_epigenetic_changes&oldid=3352’
Creative Commons Attribution-ShareAlike
Powered by MediaWiki