Fight Aging!

The immune system is deeply integrated into tissue function throughout the body. This goes far beyond merely identifying and chasing down invaders such as fungi, bacteria, and viruses. Immune cells of various types also help to coordinate tissue maintenance, regeneration from injury, and the destruction of damaged, cancerous, and senescent cells. In the brain, immune cells are involved in the maintenance and alteration of synaptic connections between neurons. Immune cells mediate inflammatory signaling, and that signaling is in turn highly influential on the behavior of other cells, altering tissue function, particularly when inflammation becomes chronic.

One possibly overly simplistic view of the evolution of the immune system is that its present state is a balance between (a) providing a good-enough defense against pathogens and errant cells, and (b) minimizing harmful side-effects resulting from the inflammatory response. Too aggressive a response and individuals will lapse into chronic inflammation and early death. Too little of a response, and the pathogens win, again causing early death. Somewhere there is a happy medium that allows enough individuals to reproduce to ensure evolutionary success. But there are likely many other trade-offs under constant selection pressure, as discussed in today's open access paper.

Functional conservation in genes and pathways linking ageing and immunity

At first glance, longevity and immunity appear to be different traits that have not much in common except the fact that the immune system promotes survival upon pathogenic infection. Substantial evidence however points to a molecularly intertwined relationship between the immune system and ageing. Although this link is well-known throughout the animal kingdom, its genetic basis is complex and still poorly understood.

In this review, we combined curation and analysis of orthologs between D. melanogaster, C. elegans, mice, and humans to reveal that genes currently known to be pleiotropically involved in immunity, lifespan, and ageing reside in a few core pathways mediating the immuno-ageing interplay. We identified 7 evolutionarily conserved signalling cascades, the insulin/TOR network, three MAPK (ERK, p38, JNK), JAK/STAT, TGF-β, and Nf-κB pathways that act pleiotropically on ageing and immunity. However, we highlight that these pathways not only cross-talk, but also clearly act pleiotropically to regulate pathogen resistance, lifespan, and ageing among many other physiological processes such as metabolism and stress resistance.

Our review demonstrates that loss of immune homeostasis is a central determinant of ageing across diverse phyla. Yet, whether immunosenescence and the age-associated decline in other traits is a cause or result of ageing remains a fundamental problem difficult to resolve. Knowing the exact time and place of changes related to immunity and ageing would be a huge step in answering this question. Moreover, how environmental effects, including life-long pathogenic challenges, variation in the microbiome, or nutrition affect age-related changes in immunity is poorly understood. To date most studies are restricted in resolution, particularly in terms of analysed tissues, time points, phenotypes, and experimental conditions. Cutting-edge technologies such as single-cell sequencing can be useful in that respect and could be utilized to characterize molecular changes during ageing and infection in specific cell types. In combination with genome-wide CRISPR knockout screens, new immuno-ageing genes can be discovered and the cross-talk between immunity and ageing further deciphered.

Currently, the level of detail needed to solve the causality enigma of ageing is likely not achievable in humans but may be addressed in shorter lived model organisms that are easier to manipulate. Once we understood ageing at this unprecedented level, it will be possible to optimize lifestyle factors and emerging drug therapies treating senescence to facilitate healthy ageing and extend lifespan.