Aging: genes/diseases/hallmarks

As a follow-up to the Cell article "From geroscience to precision geromedicine" (https://lnkd.in/gjth6AhB), there is a great 2022 article 💡 in Aging (Aging-US) by Alex Zhavoronkov and colleagues that neatly captures the genes/diseases/hallmarks relationships (https://lnkd.in/g6VVjKBX).

🧬 The study looks for genes that hit multiple hallmarks of aging, making it more likely that such targets would impact aging itself. In addition, it looks at the role of these genes in diseases, aging and non-aging-related. This triangulation enables the identification of diseases that can be addressed by targeting genes that also affect the hallmarks of aging. My understanding is that this approach powered the TNIK program at Insilico Medicine (which completed a successful Phase 2a for idiopathic pulmonary fibrosis).

Having said that, the role of the hallmarks still feels a little unclear as a framework for understanding/addressing aging. Some are akin to mechanisms of action (although even they need to be explained by more granular mechanisms, e.g., loss of proteostasis), some are umbrella terms (e.g., chronic inflammation), and others float in between, all at different levels of description, from telomere attrition to dysbiosis. The relationships between the hallmarks and age-related diseases are fuzzy. We need a clearer picture of their relationships. And connect the whole framework to metrics (e.g., frailty, intrinsic capacity, etc.).

Figure: Ranking of the top-100 gene set for AADs under high confidence settings. The ranking of the targets in AADs and NAADs are colored in blue-white and red-white thermal scales respectively. High color intensity stands for high ranking. The lowest ranking was capped at 100. Targets associated with the hallmark(s) of aging are labeled in green. Abbreviation: COPD: Chronic obstructive pulmonary disease.