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