View source for Aging-related epigenetic changes

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.<ref>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 [https://doi.org/10.1016/j.arr.2024.102204 DOI: 10.1016/j.arr.2024.102204]</ref>
== Aging-related epigenetic changes, their impacts on gene expression, and the functional consequences thereof ==
(According to Wu et al., 2024<ref>Wu, Z., Zhang, W., Qu, J., & Liu, G. H. (2024). Emerging epigenetic insights into aging mechanisms and interventions. Trends in Pharmacological Sciences. PMID: 38216430 [https://doi.org/10.1016/j.tips.2023.12.002 DOI: 10.1016/j.tips.2023.12.002]</ref>)
{| class="wikitable"
|+  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.
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! '''Epigenetic change''' !! Gene expression!! Functional consequence !! Refs
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| Decreased DNA 5mC || Upregulated ''CDKN2A'' (p16) || Accelerated senescence of human cancer cells || <ref>Wang L.
et al.
Exploiting senescence for the treatment of cancer.
Nat. Rev. Cancer. 2022; 22: 340-355</ref>
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|                   || Upregulated APP and BACE1 ||Increased Aβ production in human neuroblastoma cells || <ref>Wu Z.
et al.
Stress, epigenetics, and aging: unraveling the intricate crosstalk.
Mol. Cell. 2023; 84: 34-54</ref>
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| Decreased DNA 5mC and H3K9me3, increased H3K36me3 || Upregulated endogenous retrovirus (ERV) || Accelerated human MSC senescence || <ref>Liu X. et al. Resurrection of endogenous retroviruses during aging reinforces senescence. Cell. 2023; 186: 287-304</ref>
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| Decreased DNA 5mC, H3K9me3 and H4K20me3, increased H3K27ac and H3K4me1 || Upregulated PSG genes || Accelerated human MSC senescence || <ref>Liu Z.
et al.
Large-scale chromatin reorganization reactivates placenta-specific genes that drive cellular aging.
Dev. Cell. 2022; 57: 1347-1368</ref>
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| Decreased H3K9 and H3K36 methylation || Upregulated SASP factors, p16, and CDKN1A (p21) || Bleomycin-induced senescence of human prostate stromal cells || <ref>Zhang B.
et al.
KDM4 orchestrates epigenomic remodeling of senescent cells and potentiates the senescence-associated secretory phenotype.
Nat. Aging. 2021; 1: 454-472</ref>
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| Decreased H3K9me3 and H3K27me3 || Upregulated LINE-1 || Accelerated senescence of primary fibroblasts derived from patients with progeroid syndromes  ||<ref>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</ref>
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| Decreased heterochromatin and LAD, increased chromatin accessibility || Upregulated LINE-1 || Accelerated human MSC senescence || <ref>Bi S.
et al.
SIRT7 antagonizes human stem cell aging as a heterochromatin stabilizer.
Protein Cell. 2020; 11: 483-504</ref>
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| Decreased RNA m<sup>6</sup>A || Downregulated MIS12 || Accelerated human MSC senescence || <ref>Wu Z.
et al. METTL3 counteracts premature aging via m6A-dependent stabilization of MIS12 mRNA. Nucleic Acids Res. 2020; 48: 11083-11096</ref>
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|  || Downregulated NPNT || Accelerated human myotube senescence || <ref>Wu Z. et al. m6A epitranscriptomic regulation of tissue homeostasis during primate aging. Nat. Aging. 2023; 3: 705-721</ref>
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| Increased circRREB1 || Upregulated FASN, MMP13, p16, p21, and TP53 (p53) || Progression of chondrocyte senescence and OA pathogenesis in mice || <ref>Gong Z. et al. CircRREB1 mediates lipid metabolism related senescent phenotypes in chondrocytes through FASN post-translational modifications. Nat. Commun. 2023; 14: 5242</ref>
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| Increased DNA 5mC || Downregulated ELOVL2 || Aging of human fibroblasts || <ref>Li X. et al. Lipid metabolism dysfunction induced by age-dependent DNA methylation accelerates aging. Signal Transduct. Target. Ther. 2022; 7: 162</ref>
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| Increased DNA 6mA || Upregulated heat stress response genes || Transgenerational longevity of Caenorhabditis elegans induced by heat shock || <ref>Wan Q.L. et al. N(6)-methyldeoxyadenine and histone methylation mediate transgenerational survival advantages induced by hormetic heat stress. Sci. Adv. 2021; 7eabc3026</ref>
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| Increased H3K14ac || Upregulated CDKN2B (p15) || Accelerated human MSC senescence || <ref>Wang W. et al. A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence. Sci. Transl. Med. 2021; 13eabd2655</ref>
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| Increased H3K27ac and H3K4me1 || Upregulated HMGB2 || Rejuvenation of senescent human MSCs and alleviation of OA in aged mice || <ref>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</ref>
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| Increased H3K27ac and H3K9ac || Upregulated Aβ || Progression of AD-related degeneration || <ref>Nativio R. et al.An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer's disease. Nat. Genet. 2020; 52: 1024-1035</ref>
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| Increased H3K4me3 || Upregulated p21 || Accelerated human MSC senescence || <ref>Yan K. et al. SGF29 nuclear condensates reinforce cellular aging. Cell Discov. 2023; 9: 110</ref>
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| Increased histone acetylation || Upregulated p16 and p53 || Accelerated senescence of human cancer cells || <ref>Wang L. et al. Exploiting senescence for the treatment of cancer. Nat. Rev. Cancer. 2022; 22: 340-355</ref>
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| Increased miR-145 || Downregulated semaphorin-3A || Alleviation of heart aging || <ref>Wagner J.U.G.et al.Aging impairs the neurovascular interface in the heart. Science. 2023; 381: 897-906</ref>
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| Increased miR-31 || Repression of CLOCK and activation of MAPK/ERK signaling || Accelerated skin aging || <ref>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</ref>
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| Increased RNA m<sup>5</sup>C || Repressed cGAS-STING activity || Decreased IFN-β || <ref>Chen T. et al. NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance. Cell Metab. 2023; 35: 1782-1798</ref>
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| Increased RNA m<sup>6</sup>A || Downregulated CDKN1C (p57) || Alleviated MSC senescence, improved MSC survival and angiogenesis, and enhanced cardioprotective effect against myocardial infarction in mice || <ref>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</ref>
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|  || Upregulated CYP1B1 || Accelerated human MSC aging and onset of OA in mice || <ref>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</ref>
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| Increased RNA m<sup>6</sup>A and m<sup>5</sup>C || Upregulated p21 || Oxidative stress-induced senescence of human cancer cells || <ref>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</ref>
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== 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.<ref>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</ref> 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 ==
<references />
[[Category:Main list]]
[[Category:Drafts]]
[[Category:Aging pathways and hallmarks]]