'Hallmarks of Aging' Series Part VI: Integrating the Aging Hallmarks
Getting older isn't an isolated process.
Greetings!
Last week, I published part V in an ongoing series on the “Hallmarks of Aging.”1
If you want to read (or re-read) previous installments in this series, here are part I, part II, part III, and part IV.
This week, we’ll wrap up the series with a discussion on the integration of the aging hallmarks and how they interact to influence health and aging.
Integrating the hallmarks 🧬
The 12 aging hallmarks are not isolated but rather, interdependent, with each hallmark influencing and being influenced by others. There’s considerable crosstalk among the dozen aging hallmarks. For example:
Genomic instability, including telomere shortening, can lead to epigenetic alterations and also contributes to the loss of proteostasis due to the production of mutated proteins.
Telomere shortening triggers cellular senescence, which is associated with the loss of mitochondrial function and the production of the senescence-associated secretory phenotype (SASP) and the production of factors that promote chronic inflammation.
Epigenetic changes can impact genomic stability and mitochondrial function. They also contribute to the loss of proteostasis by affecting gene regulation.
Loss of proteostasis results in the accumulation of misfolded proteins, which can induce cellular senescence. It can also impact autophagy, further exacerbating proteostasis dysfunction.
Deregulated nutrient sensing, such as the mTOR pathway, can affect mitochondrial function and cellular senescence. It also contributes to the accumulation of senescent cells and inflammation.
Mitochondrial dysfunction can result from mutations in mitochondrial DNA (mtDNA) and can contribute to genomic instability. It also affects cellular energy production and can promote inflammation.
Cellular senescence can be triggered by DNA damage and telomere attrition. Senescent cells secrete SASP factors that promote inflammation and impact neighboring cells.
Altered communication between cells can result from changes in the extracellular matrix (ECM) and cellular junctions. It contributes to chronic inflammation and affects tissue repair.
Chronic inflammation, often referred to as “inflammaging”, can be induced by various hallmarks, including genomic instability, mitochondrial dysfunction, and cellular senescence. Inflammation, in turn, impacts multiple organ systems as we’ve discussed extensively, and is probably one of the primary causes of aging and disease.
Cellular senescence can also result from chronic inflammation, creating a feedback loop. Senescent cells promote inflammation, and inflammation, in turn, accelerates the accumulation of senescent cells.
Dysbiosis, or an imbalance or perturbation in the gut microbiome, can result from mutations in intestinal cells and also contribute to inflammation. Specific microbial proteins and metabolites can cause DNA mutations.
Stem cell exhaustion can be a consequence of multiple hallmarks, including altered nutrient sensing and chronic inflammation. It impairs tissue regeneration and repair.
The interconnectedness of these hallmarks is also reflected in anti-aging interventions.
Many interventions simultaneously target multiple hallmarks. For example, activators of sirtuins — signaling proteins with roles in metabolic regulation — can impact genomic instability, epigenetic alterations, proteostasis, autophagy, nutrient sensing, and mitochondrial dysfunction.
Similarly, spermidine, a naturally occurring compound, affects multiple hallmarks, including genomic instability, loss of proteostasis, autophagy, cellular senescence, and inflammation.
The hallmark hierarchy ⛰️
While each hallmark can be individually targeted to yield benefits for healthspan and lifespan, there exists a hierarchy among them. This hierarchy helps us understand their relative importance in aging.
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