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Living without ageing: myth or reality?

Pierre-Marie Lledo
Pierre-Marie Lledo
Research Director at CNRS, Head of Department at Institut Pasteur, and member of the European Academy of Sciences
Key takeaways
  • Numerous investments and research projects are aimed at reinvigorating biomedical research to better understand the mysteries of longevity.
  • Controlling the ageing process means avoiding all the diseases that arise from the wear and tear of our organs, such as neurodegenerative diseases.
  • It could be possible to reverse the ageing process by reprogramming the cells to make them younger or by changing the blood composition.
  • INSEE estimates that in France, at least 11% of children born after 2000 can hope to become centenarians or even 'supercentenarians'.
  • But if we live forever, we should ask ourselves whether we will die of boredom or depression.

In recent years, large sums of mon­ey have been poured into rein­vig­o­rat­ing bio­med­ical research to bet­ter under­stand age­ing. This new inter­est com­ple­ments pre­vi­ous efforts to under­stand the mys­ter­ies of longevi­ty. Since life expectan­cy is increas­ing over­all, the chal­lenge is to ensure that these added years are healthy. To achieve this goal, sci­en­tists are being asked to push back the wall of nat­ur­al longevi­ty1 so that we can live com­fort­ably beyond 115 years old2. Accord­ing to age­ing spe­cial­ists, this is no longer a utopic quest as it was back in the days of Gil­gamesh or Faust. On the oth­er hand, if it were to become a real­i­ty, this hope would sub­ject our lives, and above all the bal­ance of our soci­eties which are so sen­si­tive to demo­graph­ic change, to immea­sur­able upheaval. Let’s take a look at the sci­en­tif­ic and soci­etal aspects of this quest for eter­nal youth with­out fur­ther ado.

Will we be able to live in good health beyond 100?

Grow­ing at the rate of two years per decade, our life expectan­cy has already more than dou­bled. While it was only 27 years for a man and 28 years for a woman in 1750, it is now 80 and 86 years respec­tive­ly in France3. To under­stand this spec­tac­u­lar phe­nom­e­non, it is impor­tant to note that there has been sig­nif­i­cant progress in the sur­vival rates of chil­dren in the first few years after birth. More pre­cise­ly, it is because we were able to com­bat infant mor­tal­i­ty effec­tive­ly through vac­ci­na­tion and hygiene mea­sures under the lead­er­ship of Louis Pas­teur, and then a lit­tle lat­er through the use of antibi­otics thanks to the dis­cov­er­ies of Alexan­der Flem­ing, that aver­age life expectan­cy has increased. More recent­ly, it is the age of death that has been the new tar­get of researchers, with two objec­tives in mind: to improve the qual­i­ty of life of old­er peo­ple, and to reduce the bur­den on health sys­tems to main­tain the eco­nom­ic and social sta­bil­i­ty of our age­ing societies.

Con­trol­ling the age­ing process means avoid­ing all the dis­eases that arise from the wear and tear of our organs.

How­ev­er, the recipe is more com­plex than it seems. Con­trol­ling the age­ing process or, to be more pre­cise, pre­vent­ing it from threat­en­ing the exis­tence of indi­vid­u­als, means want­i­ng to avoid all the dis­eases that arise from the wear and tear of our organs: neu­rode­gen­er­a­tive dis­eases for the brain, rheuma­tism for the joints, car­dio­vas­cu­lar dis­eases for the heart, etc. If this objec­tive were to be achieved, like Dori­an Gray’s wish, we would remain eter­nal young peo­ple wait­ing for an acci­den­tal death to put an end to our exis­tence. So, myth or reality?

The biology of ageing is a young science!

Many com­pa­nies that see huge prof­its ahead are invest­ing in lab­o­ra­to­ries that focus on the study of age­ing. Google founders Lar­ry Page and Sergey Brin made the foun­tain of youth their ulti­mate quest by cre­at­ing Cal­i­co Life Sci­ences and Ver­i­ly Life Sci­ences. More recent­ly, Sam Alt­man (of Open​.AI) has just invest­ed $180 mil­lion in a com­pa­ny that is try­ing to delay death, and the Cal­i­forn­ian start-up Altos Lab has raised more than $3 bil­lion by 2022 to reverse cel­lu­lar age­ing. This start-up even had the lux­u­ry of recruit­ing the 2012 Nobel Prize win­ner for Med­i­cine, Pro­fes­sor Shinya Yamana­ka4.

While it is easy to under­stand this craze, it is also easy to appre­ci­ate its con­se­quences for all the play­ers in the research field. Indeed, this new obses­sion is divert­ing atten­tion from work pre­vi­ous­ly ded­i­cat­ed to the treat­ment of age-relat­ed dis­eases to a bet­ter under­stand­ing of the mech­a­nisms of age­ing. Ini­ti­at­ed in the 1990s, this research used sim­ple organ­isms such as a small worm, the nema­tode Caenorhab­di­tis ele­gans, or the fruit fly (Drosophi­la melanogaster) as study mod­els. While study­ing the sur­vival mech­a­nisms of the nema­tode exposed to dif­fi­cult con­di­tions, Gary Ruvkun dis­cov­ered the exis­tence of a lethar­gic phase called the “dauer stage”. This sta­sis allows the nema­tode to sur­vive by slow­ing down its metab­o­lism in a sim­i­lar way to the mech­a­nism that con­trols insulin secre­tion in humans. 

At the same time, a mol­e­c­u­lar biol­o­gist, Cyn­thia Keny­on, man­aged to dou­ble the life expectan­cy of the same worm by mutat­ing a gene that is also involved in the pro­duc­tion of an insulin-like growth fac­tor. Not sur­pris­ing­ly, this renowned researcher was sub­se­quent­ly recruit­ed by Cal­i­co to become its vice-pres­i­dent. Since this ear­ly work, a mul­ti­tude of stud­ies have been devel­oped by a grow­ing com­mu­ni­ty of sci­en­tists com­mit­ted to extend­ing the life span.

Treating ageing: a revolution in biological sciences? 

Age­ing is a suc­ces­sion of changes respon­si­ble for alter­ations that accu­mu­late with age, but it must be dis­tin­guished from dis­ease. Ini­tial­ly pro­posed in the 2010s, the biol­o­gy of age­ing dis­tin­guish­es a list of char­ac­ter­is­tics includ­ing genome insta­bil­i­ty, pro­gres­sive short­en­ing of telom­eres, epi­ge­net­ic alter­ations, mito­chon­dr­i­al dys­func­tion, mis­reg­u­la­tion of pro­tein fold­ing, dereg­u­la­tion of nutri­ent sens­ing, cel­lu­lar senes­cence, deple­tion of stem cell turnover and defects in inter­cel­lu­lar com­mu­ni­ca­tion. Since then, oth­er mark­ers have been added to the list, such as com­pro­mised autophagy, dereg­u­la­tion of splic­ing, a dis­turbed micro­bio­me and more or less chron­ic inflam­ma­tion. The addi­tion of these new fac­tors, at least for the last two, sup­ports the idea of a holis­tic view of the human being accord­ing to which “the whole is more than the sum of its parts”5. We would only be a holo­biont, i.e. an enti­ty formed by dif­fer­ent species that cohab­it to form a sin­gle eco­log­i­cal enti­ty. In oth­er words, we would be the prod­uct, not only of our genes, but of a mutu­al­is­tic sym­bio­sis between us (the host) and our guests (the micro­bio­me), and age­ing would also depend on this frag­ile balance.

So how might the micro­bio­me, or its mir­ror image as our immune sys­tem, con­tribute to the biol­o­gy of age­ing? We know that the immune sys­tem recog­nis­es haz­ards of all kinds through innate recep­tors that dif­fer­en­ti­ate self from non-self. Micro­bial agents, cel­lu­lar debris or nutri­ents inter­act with recep­tors that trig­ger the innate immune response known to reduce autophagy. The patholo­gies asso­ci­at­ed with age­ing there­fore cor­re­spond to this chron­ic state of autophagy dys­reg­u­la­tion. This results in the accu­mu­la­tion of intra­cel­lu­lar waste prod­ucts and a chron­ic inflam­ma­to­ry response – a self-sus­tain­ing process that would lead to the decline of the organism.

There is anoth­er line of research that is cur­rent­ly very much in vogue: mak­ing age­ing process­es reversible. We now know how to repro­gramme cells to make them younger, and my lab­o­ra­to­ry, along with oth­ers, has suc­ceed­ed in demon­strat­ing that brain age­ing can be reversed by chang­ing the blood com­po­si­tion of elder­ly sub­jects6. Today, we are able to repro­gram mol­e­c­u­lar process­es to reju­ve­nate nerve cells in the brain7. This research is already prov­ing that organ­isms such as mice can gain more than a third of their life and main­tain good men­tal and phys­i­cal health.

Longer life expectancy, and afterwards?

INSEE esti­mates that in France, at least 11% of chil­dren born after 2000 can expect to become cen­te­nar­i­ans or even ‘super­cente­nar­i­ans’. The num­ber of cen­te­nar­i­ans has explod­ed since the 1960s: from 450 at the time, there are now almost 30 000, near­ly 90% of whom are women. Demog­ra­phers’ mod­els pre­dict that there could be thir­teen times as many by 20608.

INSEE esti­mates that in France, at least 11% of chil­dren born after 2000 can expect to become cen­te­nar­i­ans or even supercentenarians.

In addi­tion to these over­ly opti­mistic esti­mates, it should be remem­bered that life expectan­cy is not increas­ing uni­form­ly across the plan­et. In France, it has increased only very slight­ly in recent years, while in the Unit­ed States it is falling at a wor­ry­ing rate9. Since the 1970s, progress in the pre­ven­tion of car­dio­vas­cu­lar dis­ease has made it pos­si­ble to sig­nif­i­cant­ly reduce mor­tal­i­ty by reduc­ing this type of dis­ease, but today the mar­gins of progress in this pre­ven­tion are min­i­mal. Their con­tri­bu­tion to improv­ing life expectan­cy is there­fore becom­ing negligible.

If sci­en­tif­ic progress can give us hope that one day we will no longer die of old age, then what will we die of? « To die of old age is a rare, sin­gu­lar and extra­or­di­nary death », wrote Michel de Mon­taigne in an essay on age10. As Mon­taigne thought, we would then only know acci­den­tal, bru­tal deaths or cho­sen deaths. In the lat­ter case, death would not be the result of weari­ness with regard to suf­fer­ing or ill­ness – since they would no longer exist – but quite sim­ply of bore­dom, depres­sion, or spleen caused by the tire­less and insipid rep­e­ti­tion of days. After the sci­en­tif­ic promise of eter­nal youth, are we con­demned to assist­ed suicide?

1A true « bio­log­i­cal wall », the nat­ur­al lim­it reached by the old­est per­son in the world is still Jeanne Cal­ment – 122 years and 164 days.
2Peo­ple who reach the age of 115 are called super­cente­nar­i­ans.
3In con­trast, healthy life expectan­cy ranks 10th in Europe at 64 years for men and 65 years for women.
4A Japan­ese researcher who has demon­strat­ed that cells can be repro­grammed, using a cock­tail of just four genes, to become embry­on­ic cells.
5A max­im attrib­uted to the philoso­pher and poly­math Aris­to­tle (384–322 BC).
6Moigneu C, Abdel­laoui S, Pfaf­fenseller B, Wol­len­haupt-Aguiar B, Chiche A, Kuper­wass­er N, Pedrot­ti Mor­eira F, Li H, Oury F, Kapczin­s­ki F, Lle­do PM and Kat­sim­par­di L (2023). Sys­temic GDF11 atten­u­ates depres­sion-like phe­no­type in aged mice via autophagy, Nature Aging 3, 213–228.
7Kat­sim­par­di L, Kuper­wass­er N, Camus C, Moigneu C, Chiche A, Tolle V, Li H, Koko­vay E and Lle­do P‑M (2019). Sys­temic GDF11 stim­u­lates the secre­tion of adiponectin and induces a calo­rie restric­tion-like phe­no­type in aged mice. Aging Cell e13038. doi: 10.1111/acel.13038.
8How­ev­er, life expectan­cy in the Euro­pean Union is decreas­ing for the sec­ond year in a row, fol­low­ing a larg­er decline between 2019 and 2020. Com­pared to 2020, life expectan­cy for women and men has decreased by 0.3 years. In 2021, life expectan­cy is 82.9 years and 77.2 years for men. The high­est life expectan­cy at birth was record­ed in Spain (83.3 years), Swe­den (83.1 years), Lux­em­bourg and Italy (both 82.7 years), while the low­est was observed in Bul­gar­ia (71.4 years), Roma­nia (72.8 years) and Latvia (73.1 years).
9The fre­quen­cy of obe­si­ty, deaths due to opi­oid depen­dence, or very unequal access to health care mean that the Unit­ed States lives on aver­age four years less than the French.
10« To die of old age is a rare, sin­gu­lar and extra­or­di­nary death, and all the less nat­ur­al than the oth­ers; it is the last and extreme kind of death; the fur­ther away from us it is, the less hope­ful it is; it is indeed the lim­it beyond which we will not go, and which the law of nature has pre­scribed not to be exceed­ed; but it is a very rare priv­i­lege to make us last until then. Michel de Mon­taigne, « On Age », The Essays, 1595.

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