Living without ageing: myth or reality?

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.

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?

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.

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.

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?