What are ageing and death from a biological point of view?

Link­ing phi­los­o­phy and biol­o­gy may seem strange. Yet there are many sub­jects where the two dis­ci­plines come into play and are, in turn, essen­tial to under­stand­ing them. Death is a per­fect exam­ple. This bio­log­i­cal real­i­ty remains an abstract con­cept until we expe­ri­ence it in our own lives. But, how­ev­er abstract it may be, death is based on a bio­log­i­cal reality.

Clé­mence Guiller­main. It’s a com­pli­cat­ed ques­tion, but I think we need to clar­i­fy what we mean by death, age­ing or end of life. The philoso­pher of sci­ence Philippe Hune­man has done a lot of work on the phi­los­o­phy of death. In his lat­est book¹, he writes that the word ‘death’ in many lan­guages des­ig­nates at least three dif­fer­ent things: a state, a process and an event. In French “la mort” is the state of being of some­thing that has died and there­fore was once alive. It is a process in the sense that, at a giv­en moment, the organ­ism begins to die and grad­u­al­ly dies until it is declared dead. And it is an event in the sense that we can iden­ti­fy, at least in the­o­ry, a pre­cise moment when the organ­ism dies.

To under­stand what death is, we need to under­stand both this event and the process­es by which we arrive at it. But how can we under­stand them if even the cri­te­ria for defin­ing them depend on states, con­ti­nents and even cultures?

Alex­is Gautreau. It depends some­what on the cul­ture. But, gen­er­al­ly speak­ing, we’re talk­ing about the absence of a pulse, the absence of breath­ing and a flat elec­troen­cephalo­gram. The prob­lem is that based on these cri­te­ria, there are many peo­ple who have been declared clin­i­cal­ly dead and who have “come back” to life. These famous “near-death expe­ri­ences” (NDEs) have left a pro­found impres­sion, and this is an aspect that Clé­mence’s the­sis was able to address. Books for the gen­er­al pub­lic, such as Dr Moody’s², all fea­ture the same accounts, such as the impres­sion of leav­ing one’s body or see­ing the light at the end of the tun­nel, regard­less of a person’s cul­ture or beliefs. We all have a psy­che­del­ic hor­mone, dimethyl­trypt­a­mine (DMT), which is released in the final moment and helps us to make the tran­si­tion, the great jour­ney. There are very few stud­ies on DMT, but it’s fas­ci­nat­ing. DMT admin­is­tra­tion induces a phys­i­o­log­i­cal state com­pa­ra­ble to that expe­ri­enced by peo­ple who have had an NDE³. Why would a mech­a­nism like this have evolved? Whether or not you feel reas­sured when you make your final jour­ney should be irrel­e­vant from a Dar­win­ian selec­tion stand­point. If the hypoth­e­sis that DMT is released in the final moment is true, which is extreme­ly dif­fi­cult to prove, there must be anoth­er func­tion for this hormone…

CG. This is where one ques­tion leads to anoth­er, and the two tend to be con­fused. Accord­ing to Ernst Mayr⁴, twen­ti­eth cen­tu­ry biol­o­gy is based on two main approach­es, with dis­tinct meth­ods and ques­tions. The biol­o­gy of ulti­mate caus­es (evo­lu­tion­ary biol­o­gy) seeks to under­stand not only why we die, but also why bio­log­i­cal char­ac­ter­is­tics such as death and age­ing have not been elim­i­nat­ed by nat­ur­al selec­tion. The biol­o­gy of prox­i­mate caus­es (func­tion­al biol­o­gy), on the oth­er hand, asks how an organ­ism dies, i.e. what are the under­ly­ing mech­a­nisms that cause an indi­vid­ual and its organs to pro­gres­sive­ly dete­ri­o­rate until it final­ly dies.

AG. Research depends on grants and there­fore on fund­ing. Pre­vi­ous­ly, there were only grants for dis­eases as such: can­cers, car­dio­vas­cu­lar and neu­rode­gen­er­a­tive dis­eases. Over the last ten years or so, there has been a very strong focus on age­ing itself, because we’ve realised that even if we had a mir­a­cle cure for can­cer or Alzheimer’s, we’d still die of oth­er things soon after­wards. So, what we need to do is put off death by slow­ing down the age­ing process. The aim is to post­pone all age-relat­ed ill­ness­es, such as all those I’ve men­tioned, so that we can not only live long, but live long in good health!

CG. Yes, you’re refer­ring to Robert Wein­berg⁵, who showed that even if we man­aged to cure all can­cers (the sec­ond lead­ing cause of death in France and the Unit­ed States), we would only man­age to increase life expectan­cy by about three years.

AG. In any case, the objec­tive has always been to find out how we die rather than why, even though there is now all this fund­ing devot­ed to longevity.

CG. And age­ing, the process that leads us all irrev­o­ca­bly towards death, rais­es many ques­tions. I’ve done a lot of work on it, and even defin­ing it is com­pli­cat­ed. When do we start to age? Is it from birth, from sex­u­al matu­ri­ty or from a form of decline that we need to be able to iden­ti­fy? More recent mod­els stip­u­late that our age­ing begins with one or more spe­cif­ic events, which could be, as Michael Rera, one of my col­leagues, has shown, a dras­tic increase in intesti­nal per­me­abil­i­ty⁶, for exam­ple. This type of phe­nom­e­non would be an indi­ca­tion of entry into an end of life. 

AG. Intesti­nal per­me­abil­i­ty is a chron­ic dis­ease in the elder­ly, which dra­mat­i­cal­ly stim­u­lates the immune sys­tem. We expect all the organs to func­tion less well as we age. In fact, it is often the immune sys­tem that works too hard. It becomes less dis­crim­i­nat­ing and starts attack­ing our own organs. “Autoim­mune” dis­eases dam­age elder­ly people’s bod­ies at a rate that has increased in recent decades. It would seem, how­ev­er, that it is still pos­si­ble to post­pone or slow down the age­ing process. There is a very sim­ple treat­ment that works in many species, from sin­gle-cell yeasts to flies, worms, and mice. By restrict­ing the food intake of the organ­ism quite dras­ti­cal­ly, each species will live a lit­tle longer⁷. After that, the sim­pler the organ­ism, the greater the gain. In yeast, the lifes­pan is mul­ti­plied by three. In mice, the gain is only 50%. In humans, this has obvi­ous­ly not been demon­strat­ed, because we already live to be 80 years old on aver­age, and nobody has done the exper­i­ment. But by gain­ing 50%, we would go from an aver­age life expectan­cy of 80 to 120 years. Anoth­er exper­i­ment has shown that we can iso­late mutant vari­a­tions that live longer⁸. This comes as a huge sur­prise because mutants are usu­al­ly seen as “unhealthy”. But most of these mutants that live longer have genes that code for pro­teins involved in con­sum­ing the ener­gy pro­vid­ed by food. The two sets of find­ings are entire­ly con­sis­tent with one anoth­er. It’s as if our metab­o­lism had been pro­grammed to make a cer­tain num­ber of turns and then we had a pro­gramme encod­ed in our genes to make us die.

AG. If this pro­gramme exists, it means that it has been con­served and shaped dur­ing the evo­lu­tion of species. What would be the evo­lu­tion­ary advan­tage of mak­ing us die ear­li­er? It seems that the price to be paid for the increased longevi­ty result­ing from calo­rie restric­tion is in the area of repro­duc­tion. In fact, if we live with a reduced metab­o­lism, we will cer­tain­ly be able to slow down our tachome­ter, but at the same time we will be less effi­cient over­all, par­tic­u­lar­ly when it comes to find­ing a sex­u­al part­ner, cop­u­lat­ing, pro­cre­at­ing, and bring­ing our young to sex­u­al matu­ri­ty. There’s a cer­tain log­ic in mak­ing us live life to the full for 40 years – the time it takes to do all that – and then let­ting our capac­i­ties slow­ly dete­ri­o­rate. Whether our capac­i­ties dete­ri­o­rate slow­ly or rapid­ly after­wards, it remains out­side the scope of Dar­win­ian selec­tion in any case.

C.G. All this was con­cep­tu­alised by Thomas Kirk­wood, who devel­oped one of the three major the­o­ries of evo­lu­tion­ary biol­o­gy on age­ing. This is the so-called dis­pos­able soma the­o­ry, which is based on the idea that each indi­vid­ual has a cer­tain amount of ener­gy, which he or she choos­es to allo­cate pref­er­en­tial­ly, either to sur­vival, or to main­tain­ing the organ­ism, or to repro­duc­tion or oth­er mech­a­nisms. The choice made would have an impact on the others.

AG. The upshot of all this is that there are mutants that can live longer. These mutants are in our genes, and our genes code for pro­teins. And pro­teins are the tar­gets of phar­ma­ceu­ti­cal mol­e­cules. In the­o­ry, there­fore, the longevi­ty effect could be repro­duced using a mol­e­cule tar­get­ing the pro­teins that reg­u­late our metab­o­lism. Proof of con­cept has now been demon­strat­ed. Using rapamycin, we’ve man­aged to make mice live longer⁹. We could first repro­duce and then try to live longer thanks to such a drug in the sec­ond half of life.

CG. I would qual­i­fy that state­ment slight­ly, in the sense that, if you look at the major stud­ies on longevi­ty, the genet­ic com­po­nent of life expectan­cy is quite small¹⁰. On the oth­er hand, the results obtained on species such as nema­todes and even mice are quite extra­or­di­nary. For the moment, we still have the impres­sion that things are more com­plex, and that it is still dif­fi­cult to find a gene or a small num­ber of genes in the more devel­oped species that can sig­nif­i­cant­ly improve lifespan.

AG. Obvi­ous­ly, I agree with you that this is just wish­ful think­ing for the time being. But what is cer­tain today is the close link between longevi­ty and diet. What makes peo­ple live longer is calo­rie restric­tion. And this is very sim­i­lar to the mea­sures tak­en to com­bat can­cer or dia­betes, where we have to stop feed­ing peo­ple dis­pro­por­tion­ate amounts of sug­ar. We may have pro­grammes to ensure that we live to 120 – the max­i­mum age of the human species – but it is these same pro­grammes that put the brakes on the many tumours that are con­stant­ly devel­op­ing in our bod­ies. Senes­cence, for exam­ple, pre­vents many cells from form­ing tumours by irre­versibly block­ing their pro­lif­er­a­tion, but these senes­cent cells also secrete inflam­ma­to­ry mol­e­cules that cause us to age. We can’t help think­ing that there are many trade-offs of this kind, and the ques­tion is whether we’ll be able to exploit the pos­i­tive side with­out simul­ta­ne­ous­ly acti­vat­ing the neg­a­tive aspect…

Pablo Andres