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