The organellar biology of aging: A mitochondrial vantage

Aging is a progressive, multi-scale decline in physiological function driven by the accumulation of cellular and molecular damage. Mitochondrial dysfunction has emerged as an established hallmark of aging owing to its critical involvement in bringing about aging-associated changes. Oxidative damage to the organellar genome impairs its function, causing redox imbalance and energy depletion. Concurrently, defective poly (ADP-ribose) polymerase 1 (PARP1) signaling and reduced cellular NAD⁺ levels affect molecular regulators such as SIRT1 (sirtuin 1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha, which are central to mitochondrial dynamics and function. This axis does not operate in isolation but instead communicates with other organelles such as the endoplasmic reticulum, lysosome, and peroxisome to facilitate age-related changes. Most intriguingly, mitochondria also generate several retrograde signals to regulate nuclear gene expression, including the transcriptional regulators vital for mitochondrial function and other master regulators of aging. In essence, aging-associated organellar alterations, mitochondrial dysfunction, and inter-organellar crosstalk work in a loop to promote aging progression. More research in the field may unravel the mechanistic details of the organellar crosstalk that works in concert with classical aging pathways to sustain aging progression, which may help promote healthier aging.