Fight Aging!

Senescent cells accumulate in tissues throughout the body with age. Cells become senescent constantly throughout life, largely by reaching the Hayflick limit on replication, but a small number due to potentially cancerous mutations, or other forms of damage and stress. Senescent cells are rapidly removed by the immune system in youth, keeping their numbers low, but the balance between creation and destruction is disrupted with aging. There is greater stress, but perhaps more importantly the immune system becomes less efficient, less able to clear senescent cells in a timely fashion. Since senescent cells actively secrete pro-inflammatory, pro-growth signals, they are a disruptive, harmful influence on tissue structure and function with present for the long term in even comparatively small numbers.

It is fair to say that near every tissue and system in the body examined to date suffers from the late life presence of lingering senescent cells and their inflammatory secretions. These cells contribute meaningful to the onset and progression near every age-related condition. This includes the decline of the immune system into immunosenescence and inflammaging. It would be surprising indeed to find that removal of senescent cells failed to improve late life immune function in humans, considering what we know of the mechanisms involved, and the impressive array of evidence from animal studies. Even only considering the point that senescent cells encourage constant, unresolved inflammation, their removal should be beneficial to immune function.

The ageing immune system as a potential target of senolytics

The immune system is essential in protecting the body from various pathogenic mechanisms and infection, in particular, there are significant changes to immune function as we age. Recent studies have suggested that the cellular senescence of immune cells impairs clearance of pathogenic material, increasing the risk of severe infections and mortality. These processes lead to the build-up of inflammatory mediators, causing inflammageing - a state of chronic immune activation that is associated with blunted innate and adaptive immune responses. The cumulative effect of these processes triggers downregulation of immune responses, via mechanisms such as defective lymphocyte responses and a reduction in regulatory immune cells. Thus leading to deterioration of the immune system with age, termed immunosenescence. Thus, clearance of senescent immune cells could be beneficial to the immune system, as has been witnessed in other tissues. This has driven research into modalities which can delay, or reverse, these age-related immune changes.

Current senolytics aim to clear all senescent cells, regardless of their cell type, however, refining this to target specific senescent cell populations may be of benefit, by increasing the efficacy of drugs whilst reducing potential side effects, as seen in other fields such as cancer therapies. One of the major concerns of an ageing immune system is its diminished immune response, which in part is driven by senescent immune cells. This effect of an ageing immune system can be seen clinically, as older populations are at greater risk of succumbing to serious infections and have poorer efficacies with regards to vaccines. Senolytics targeting senescent immune cells may provide a solution to help improve immunity within elderly populations.

Targeting senescent immune cells has further drawn interest in the treatment of age-related diseases. Recent studies have implicated senescent immune cells in driving senescence and ageing in tissues including the liver in mouse and rat models, although the precise mechanism behind this is yet to be determined. Given these findings, it is tempting to speculate that senescent immune cells are driving similar age-related changes in other tissues and organs. Targeting senescent immune cells therapeutically could therefore provide benefits beyond that of targeting individual tissue-based senescent cell populations.

Although current senolytics may have some degree of senescent immune cell clearance, a senolytic specifically targeting senescent immune cells has not yet been developed. Given the impact of senescent immune cells on the pathophysiology of age-related disease and the diminution of the immune response, senolytics targeting these cells may have multi-faceted benefits. Additionally, whilst research is still in early stages, pre-clinical models show that senolytics could modulate a more favourable immune response to infection in older mice and humans.