The immune system and aging: a newly discovered role

By Megan Widdows

The aver­age lifespan of a human in the UK in 2020 is 81.4 years, yet every­one knows that this doesn’t mean that we will all live for exactly that length of time. In real­ity there is a lot of vari­ation in the longev­ity, or lifespan, of indi­vidu­al people. But what determ­ines this variation? 

In humans, the pro­cess of aging and our lifespan is dic­tated by a com­bin­a­tion of genet­ic and non-genet­ic factors. Some of the most import­ant non-genet­ic factors come from our envir­on­ment, espe­cially wheth­er we have access to clean air and water, healthy liv­ing con­di­tions and healthcare. 

Des­pite the import­ance of our envir­on­ment, it is estim­ated that around 25% of vari­ation in human char­ac­ter­ist­ics is due to genet­ic factors. Lots of genes that have been linked to our longev­ity, and the longev­ity of oth­er spe­cies, have func­tions to do with the main­ten­ance of our cells or DNA. How­ever, there is still lots we don’t under­stand about the genet­ics of aging. For example, we don’t know how much vari­ation there is in these genes between mem­bers of the same spe­cies, or the impact this may have on our lifespan. 

In order to answer some of these ques­tions, a group of sci­ent­ists ana­lysed the DNA of dif­fer­ent fruit flies. Over a peri­od of 35 years, these flies were select­ively bred so that they evolved to repro­duce late in their life­time, which indir­ectly increases their lifespan. The sci­ent­ists achieved this by only breed­ing flies that sur­vived to, and were fer­tile at, a rel­at­ively old age. These flies then passed on to their off­spring the genes that enabled them to live longer and repro­duce later. The cycle con­tin­ued for gen­er­a­tion after generation. 

After 35 years, the flies had evolved to have suc­cess­ful late-life fer­til­ity and their lifespan had increased by around 40–50% com­pared to flies that had not been select­ively bred. How­ever, there was a cost. They were now less able to repro­duce suc­cess­fully in early life. This is what is known as an evol­u­tion­ary trade off, where a change in one trait that increases fit­ness res­ults in a linked change in anoth­er trait, which reduces fitness. 

Using a tech­nique called Whole Gen­ome Sequen­cing, the sci­ent­ists iden­ti­fied many dif­fer­ent genes that had been affected by arti­fi­cial selec­tion for longer lives. Based on exist­ing know­ledge, the sci­ent­ists expec­ted to find an over-rep­res­ent­a­tion of genes that have already been linked to longer lifespans in oth­er stud­ies. Instead, they found that there was an over-rep­res­ent­a­tion of genes involved in immunity. 

Our immune sys­tem is fun­da­ment­al to keep­ing us healthy. Its main job is to provide pro­tec­tion from patho­gens, which are bac­teria, vir­uses or oth­er microor­gan­isms that can make us unwell. One way the immune sys­tem does this is though the pro­duc­tion of anti­mi­cro­bi­al pep­tides, small molecules that break down invad­ing pathogens. 

The study found that, as the longer-lived flies aged, the pro­duc­tion rate of these anti­mi­cro­bi­al pep­tides declined. This may sound like an unfor­tu­nate response, but it actu­ally res­ul­ted in an increased abil­ity to sur­vive fungal, bac­teri­al and vir­al infec­tions. This sug­gests that the flies may have evolved mech­an­isms of redu­cing the impact of immun­osen­es­cence, which is the gradu­al deteri­or­a­tion of the immune sys­tem that hap­pens nat­ur­ally as we age. The immune sys­tem remained fully func­tion­al in old age, pre­vent­ing dys­func­tion such as the devel­op­ment of autoim­mune dis­ease.

In con­trast, the short-lived flies had an increased pro­duc­tion of anti­mi­cro­bi­al pep­tides with old age, which led to a reduced capa­city to fight off infec­tion. This sug­gests that the flies could be suf­fer­ing from so-called immune over-activ­a­tion, where the immune sys­tem pro­duces an inap­pro­pri­ately large response to an invad­ing pathogen. 

An optim­um immune response relies on find­ing a bal­ance between effi­ciently killing patho­gens and lim­it­ing the dam­age caused by an immune response, espe­cially as a res­ult of pro­longed inflam­ma­tion. Nor­mally as an organ­ism ages, there is a reduc­tion in the abil­ity to con­trol gene expres­sion, which is the pro­cess by which the instruc­tions in our DNA are con­ver­ted into func­tion­al products such as a pro­teins. This means older organ­isms lose some of their inher­ent con­trol over the pro­duc­tion of pro­teins, includ­ing anti­mi­cro­bi­al pep­tides. In this case, this leads to excess pro­duc­tion of anti­mi­cro­bi­al pep­tides and immune over-activ­a­tion. It appears that the longer-lived flies have evolved a mech­an­ism to pre­vent this from occur­ring, which could explain their great­er longevity. 

The find­ings of this study will have ongo­ing rami­fic­a­tions in the fields of evol­u­tion­ary genet­ics and the study of aging, demon­strat­ing the import­ant role that the immune sys­tem plays in increas­ing longev­ity. This coin­cides with grow­ing evid­ence to sug­gest that aging, inflam­ma­tion and immunity are all del­ic­ately inter­twined right down to the molecu­lar level. This study will open the door to fur­ther research, includ­ing determ­in­ing how changes to the immune sys­tem can actu­ally increase life span. 

The study men­tioned in this art­icle can be found here. A gloss­ary of key terms is provided below.

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