Ageing as a disease: a new paradigm in medicine?

There have been two major revolu­tions in the slow his­tory of research on age­ing. First, was the revolu­tion in life expect­ancy at birth. If our life expect­ancy has doubled in a cen­tury, it is essen­tially because we have erad­ic­ated infant mor­tal­ity with vac­cin­a­tion, hygiene and, later, anti­bi­ot­ics. What has also increased since the 1950s, and this is the second revolu­tion, is our longev­ity – we are liv­ing longer on aver­age. Since the middle of the 20^th Cen­tury, the age at which we die has been greatly increased and our life expect­ancy has con­tin­ued to rise. This is mainly due to devel­op­ment of med­ic­a­tion to treat dis­eases of old age (dia­betes, car­di­ovas­cu­lar dis­ease, can­cer, etc.). 

On the oth­er hand, we do not neces­sar­ily age in good health. Such is because we only treat patho­lo­gies that occur in suc­ces­sion in old age. How­ever, for more than fif­teen years, my work has led me to believe that it is rather old age that we should treat as a dis­ease in its own right.

When our pro­gramme began in 2006, we star­ted from scratch by tak­ing as our research axis how we go from a “juven­ile” embryo to an age­ing indi­vidu­al. If we age, it is because our cells age. I focused on the two types of cells found in tis­sues with age: sen­es­cent cells and cells that age by depro­gram­ming. And very quickly, I real­ised that these cells had to be repro­grammed to fight age-related ill­nesses. Coin­cid­ent­ally, when I star­ted this pro­ject a Japan­ese research­er, Shinya Yaman­a­ka, demon­strated that cells could be repro­grammed to become embryon­ic cells, which encour­aged us to persevere.

In 2011, our work proved that age­ing is revers­ible. A little later, research­ers demon­strated that if you remove sen­es­cent cells from mice, you can increase their life expect­ancy. Then oth­er labor­at­or­ies, includ­ing our own, developed stud­ies on the repro­gram­ming of cells, which also made it pos­sible to increase longev­ity. With­in the sci­entif­ic com­munity work­ing on age­ing, a con­sensus has slowly emerged around nine rig­or­ously defined mark­ers of cel­lu­lar age­ing: the Hall­marks of age­ing. They enable us to pre­cisely mon­it­or the sen­es­cence of our cells and our organ­ism. This age­ing pro­cess that can also be detec­ted in the blood.

At the end of this research and test­ing pro­cess, a clear con­clu­sion emerged: when we tar­get two of the signs of age­ing in our cells, sen­es­cence, and “epi­gen­et­ic” depro­gram­ming, we increase our longev­ity and age-related dis­eases dis­ap­pear. The lat­ter are in fact only the con­sequence of the age­ing of our cells. Age­ing is the moth­er of all dis­eases, and it is there­fore the one that must be targeted. 

This obser­va­tion is now shared by many col­leagues. We now know that we can use small molecules to sup­press sen­es­cent cells that are harm­ful to tis­sues. If we sup­press these sen­es­cent cells in anim­al mod­els, we gain 30% of healthy life by delay­ing age-related ill­nesses. These devel­op­ments are under­way, and clin­ic­al tri­als are being car­ried out in some coun­tries, not­ably the United States, which is lead­ing the way on this subject. 

Amer­ic­an research­ers are lob­by­ing to set up clin­ic­al tri­als on healthy eld­erly people.

The prob­lem with these stud­ies is that, for the moment, they are only clin­ic­al tri­als on age-related patho­lo­gies: pul­mon­ary fibrosis, dia­betes, osteoarth­rit­is, etc. But the dis­ease is already there, the tis­sue is already dam­aged. The res­ults would be great­er if we could treat the patient before the dis­ease is present before the tis­sue defect is noted. And here we are really enter­ing into the field of pre­ven­tion. To be able to treat age­ing with drugs and small molecules, it must be con­sidered as a dis­ease, which is not yet the case and which poses prob­lems for doc­tors. Amer­ic­an research­ers are lob­by­ing the reg­u­lat­ory agen­cies to set up clin­ic­al tri­als on healthy – not sick – eld­erly people, to see if we can improve physiology while avoid­ing these illnesses.

There is anoth­er line of work: reju­ven­a­tion. We now know how to repro­gram cells to reju­ven­ate them, and my team was the first, more than ten years ago, to demon­strate that cel­lu­lar age­ing was revers­ible. By repro­gram­ming sen­es­cent cells and age­ing cells of cen­ten­ari­ans, we can con­vert them into cells with a reju­ven­ated physiology. Today, we can repro­gram all the cells in a mouse to reju­ven­ate them, and a hand­ful of labor­at­or­ies around the world are work­ing in this area. These tests allow the mouse to live 30% longer, in good health. Very ambi­tious inter­na­tion­al pro­jects are also being set up, with budgets of sev­er­al bil­lion dol­lars, to go even fur­ther and trans­fer these tech­no­lo­gies to humans.

Research on age­ing and reju­ven­a­tion will lead to increased life expect­ancy in the near future.

These two areas of research will inev­it­ably lead to an increase in life expect­ancy in the near future. This will prob­ably be the case in the next ten years in the United States since research­ers are already car­ry­ing out a clin­ic­al tri­al on drug repos­i­tion­ing [the reuse of drugs already on the mar­ket]. Once this research has been val­id­ated, in five or six years it will be pos­sible to pre­scribe molecules such as met­form­in, which aims to delay all age-related ill­nesses, to healthy people.

I believe that France needs to make the pre­ven­tion of age­ing a pri­or­ity without wait­ing for people to become ill as they age. If we reas­on math­em­at­ic­ally, dis­cov­er­ing a treat­ment that increases life expect­ancy by three to five years for a fatal dis­ease increases the prob­ab­il­ity of hav­ing anoth­er age-related dis­ease later. And so on. If we really con­sider old age as a dis­ease, if we treat it as such, this will make it pos­sible to avoid all age-related dis­eases at the same time. This work calls for a new medi­cine, a medi­cine based on longev­ity, a geri­at­rics 2.0 to increase life expect­ancy and make healthy longev­ity a major chal­lenge for our society.

Interview by Jean Zeid