In a recent article published in Cell, researchers proposed that 12 distinctive traits of aging are all inter-related.
In addition to being inter-related, the scientists proposed that the 12 distinctive traits of aging fulfill three criteria as follows:
(i) they become apparent with age, (ii) their experimental enhancement accelerates aging, and (iii) any therapeutic intervention on them presents the opportunity to slow down, cease or reverse aging.
These 12 distinctive aging traits were as follows: i) genomic instability, ii) telomere attenuation, iii) epigenetic changes, iv) forfeiture of proteostasis, v) macroautophagy disablement, vi) deregulation of nutrient sensing, vii) dysfunctioning of mitochondria, viiI) cellular aging, ix) stem cell fatigue, x) modulated intercellular dialogue, xi) dysbiosis, and xii) chronic inflammation.
Quoting an elaborate example, the authors described the interrelatedness of genomic instability due to telomere shortening with all 11 distinctive aging traits. For instance, it communicates to epigenetic modifiers/genes, such as methylcytosine dioxygenase 2 (TET2), through loss-of-function mutations. Likewise, the production of mutated proteins due to genomic instability results in the forfeiture of proteostasis. Via causing mutations in mitochondrial deoxyribonucleic acid (DNA), it crosstalks with mitochondrial dysfunction.
This interrelatedness also becomes evident during experimental anti-aging interventions concomitantly targeting all these traits. For instance, pleiotropic drugs, such as those based on sirtuin-activating nicotinamide adenine dinucleotide (NAD)+ precursors, weaken genomic instability via DNA repair. Similarly, the elimination of protein aggregates prevents the forfeiture of proteostasis. Other examples include epigenetic changes induced via histone deacetylation and enhanced autophagy for disabling macroautophagy.
Spermidine makes complexes with DNA to counteract genomic instability, also affects translation, reverses lymphocyte aging, prevents fatigue in muscle stem cells, helps maintain circadian rhythms, inhibits inflammation, and stimulates cancer immunosurveillance. Similarly, metformin, via a pleiotropic action, activates the nutrient scarcity sensor, adenosine monophosphate-activated protein kinase (AMPK), and brings about positive shifts in the gut bacteria. Nevertheless, any effective anti-aging intervention, e.g., lowered insulin-like growth factor (IGF-1) signaling, targets different aging traits using a variety of mechanisms across tissues to maintain the health of an organism.
Although all aging traits could be targeted one by one for noticeable benefits for the health of an organism, strikingly, this happens in a hierarchal pattern. So, the primary aging traits representing damages to the genome, telomeres, organelles, etc., accumulate over time to accelerate the aging process.
On the contrary, the antagonistic aging traits, representing a response to damage, play a more subtle role in the aging process. For instance, anabolic reactions activated by nutrient-sensing that once were beneficial in adults and contributed to organ development become pro-aging later. Likewise, reversible and slight mitochondrial dysfunction stimulates beneficial counterreactions. However, space-confined cellular aging contributes to wound healing but suppresses oncogenesis.
Once the body attains a stage where the compensation becomes unfeasible, the aggregate damage due to the two aging traits gives rise to integrative aging traits. It results in stem cell fatigue, intercellular communication changes (e.g., damage to the extracellular matrix), dysbiosis, and chronic inflammation, all of which determine the speed of aging.
Geroscience has made immense progress and developed several longevity strategies using mammalian models. For instance, heterochronic parabiosis experiments in mice have illustrated how circulating cells and hormones influence the aging process. However, it needs a critical assessment of which ones could intervene with human aging in real-world settings and the degree to which they could extend the human health span. Then, the question arises of what is best: avoiding age-deteriorating environmental factors, such as pollution and stress, adopting health-enhancing lifestyle habits, such as regular exercise & sleep, or using relatively non-specific, pleiotropic drugs, or seeking specific medical guidance.
Here it is noteworthy that specific medical treatments, such as cell-based therapies, will remain in the purview of research —would come at a higher cost with complex logistics. Moreover, since aging is not a recognized target for drug development, clinical trials evaluating anti-aging drugs will also have to mitigate age-related pathologies rather than aging.
Given the number of aging traits offering therapeutic interventions, it will be interesting to evaluate combination regimens with maxim benefits and minimum side effects. It will require a clinical assessment of an individual's genetic and phenotypic aging clocks. To date, it is unpredictable whether geroscience has many prospects. Nevertheless, further research in this domain would open new avenues for effective interventions that could improve healthy longevity.
- Lo ́ pez-Otı ́n et al. (2023). Hallmarks of aging: An expanding universe. Cell. doi: https://doi.org/10.1016/j.cell.2022.11.001 https://www.sciencedirect.com/science/article/abs/pii/S0092867422013770
Posted in: Medical Science News | Medical Research News | Miscellaneous News
Tags: Adenine, Adenosine, Aging, Autophagy, Bacteria, Cancer, Cell, Chronic, DNA, Drugs, Dysbiosis, Exercise, Fatigue, Genes, Genetic, Genome, Genomic, Growth Factor, Inflammation, Insulin, Kinase, Lymphocyte, Metformin, Mitochondria, Muscle, Oncogenesis, Pollution, Protein, Proteostasis, Research, Sleep, Stem Cells, Stress, Telomere, Translation, Wound, Wound Healing
Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.
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