Fight Aging!

Aging is caused by a number of independent issues, forms of damage and dysfunction that arise as a consequence of the normal operation of a youthful and undamaged metabolism. If these processes remained independent, aging would be a far less challenging field of study than is the case, but unfortunately, everything interacts with everything else in cellular biology. Processes of damage encourage one another, and combine in complex ways to produce shared consequences. Those consequences can in turn interact with the underlying mechanisms of damage to alter and accelerate their effects.

In today's open access paper, researchers discuss some of the interactions between cellular senescence and mitochondrial dysfunction, two quite different mechanisms of aging. Mitochondrial dysfunction is known to promote inflammatory signaling, such as via the mislocalization of mitochondrial DNA to places in which it will trigger an innate immune response. Evidence suggests that this sort of mechanism likely drives some fraction of the harmful inflammatory signaling that is produced by senescent cells. This raises interesting questions, such as whether or not strategies intended to reverse mitochondrial dysfunction will, as a side-effect, also reduce the contribution of senescent cells to degenerative aging.

Targeting Mitochondria to Control Ageing and Senescence

Ageing is associated with increased inflammation and activation of the innate immune system. This condition is known as "inflamm-ageing" and is characterised by chronic activation of JAK-STAT signalling in the circulating immune cells of elderly patients, activation of the NLRP3 inflammasome, and higher circulating levels of inflammatory mediators such as C-reactive protein, IL-6, and fibrinogen. A leading hypothesis for the origin of "inflamm-ageing" is the build-up of senescent cells with ageing, and the consequent production of a systemic senescence-associated secretory phenotype (SASP). An important support for this hypothesis comes from experiments in which aged mouse blood is transferred to young animals, which results in features of accelerated ageing. Interestingly, previous treatment of the old donors with senolytic agents reduced "inflamm-ageing" after blood exchange, and the old blood lost its pro-ageing activity. In humans, senolytic treatments also reduce the "inflamm-ageing" of patients suffering from lung fibrosis or chronic kidney disease.

Importantly, mitochondria of senescent cells are known to play a key role in triggering the SASP. In particular, depriving senescent cells of mitochondrial DNA or mitochondria altogether seriously compromises the SASP. The detailed mechanisms connecting the mitochondria of senescent cells with the SASP are still unknown. We speculate that they could be similar to the mechanisms connecting dysfunctional mitochondria with inflammation. These may include the release of cytosolic and/or extracellular mitochondrial DNA (mtDNA), mitochondrial double-stranded RNA, N-formyl peptides (a sub-product of mitochondrial protein translation), and phospholipid species such as cardiolipin, enriched in the inner mitochondrial membrane . The most studied of these components is mtDNA.

Taken together, the evidence presented in this review shows that mitochondria dysfunctions have a close relationship with ageing and cellular senescence. Several mitochondrial pathways have already been taken into consideration as potential therapeutic targets for ageing-associated diseases, and promising compounds have been developed. Future research will have to answer numerous open questions including: is it possible to completely restore mitochondrial function in senescent and aged cells? Which age- or senescence-associated aspects are the primary drivers of mitochondrial dysfunction and vice-versa? Which ones are targetable therapeutically? Answering some of these questions could get us closer to healthy ageing, with countless medical, social and economic benefits.