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Andrew Steele
π Health and biotech

Three possible ways of turning back the clocks of ageing

Andrew Steele
Andrew Steele
PhD in physics from the University of Oxford, Science Writer and Columnist at Polytechnique Insights
Key takeaways
  • Scientists now understand better than ever the fundamental biology of what causes us to grow old and, most excitingly, how we can slow down or even reverse these biological changes.
  • The study of telomerase a major aspect of the ageing research around ageing. An idea is to extend telomeres to revert cells to a more youthful form.
  • Another theory is to remove “senescent” cells (responsible for ageing) so that we may live longer and younger.
  • Finally, a solution could be cellular reprogramming, which consists of taking any cell from our body and converting it into a “pluripotent cell” to replace damaged ones.

Many of us think of the age­ing process as a fact of life. As humans, our risk of death ris­es by 10% each year thanks to the ever-tick­ing bio­log­i­cal clock of the age­ing process. Old­er peo­ple are more like­ly to suf­fer from dis­eases like can­cer and demen­tia, more like­ly to be frail, lose their sight, hear­ing or mem­o­ry, and much more besides.

How­ev­er, this process may not be so depress­ing­ly inevitable as we usu­al­ly imag­ine. Sci­en­tists now under­stand bet­ter than ever the fun­da­men­tal biol­o­gy of what caus­es us to grow old1 and, most excit­ing­ly, how we can slow down or even reverse these bio­log­i­cal changes.

Here are three ideas to watch which could one day soon be turn­ing back your bio­log­i­cal clock.

1. Telomerase: revitalising our DNA

One of the best known areas of age­ing research is study­ing ‘telom­eres’: pro­tec­tive caps which ensure the integri­ty of the ends of our DNA. How­ev­er, many cells in our bod­ies are con­stant­ly divid­ing: tis­sues like our skin, our blood and the lin­ing of our guts need to be con­stant­ly replaced due to wear and tear, and fresh­ly divid­ed new cells replace the old-timers. And unfor­tu­nate­ly, cel­lu­lar divi­sion comes at a cost to our telom­eres: they get short­er every time a cell divides.

The longer you live, the more times your cells will have divid­ed, and the short­er your telom­eres will be on aver­age. And mea­sur­ing telom­ere length isn’t just a round­about way of deter­min­ing how old you are—telomeres seem to have a causal role in age­ing too. Short­er telom­eres make age-relat­ed dis­eases more like­ly, and slight­ly mor­bid stud­ies of iden­ti­cal twins have found that the one with short­er telom­eres is like­ly to die soon­er.2

Sci­en­tists in the 1990s were thus very excit­ed by telom­erase: an enzyme which can extend telom­eres and, per­haps, make cells more youth­ful at the same time. Unfor­tu­nate­ly, its tenure as the immor­tal­i­ty enzyme didn’t last long: exper­i­ments in mice showed that telom­erase did indeed give their cells the poten­tial to divide far more times—at the cost of mas­sive­ly increas­ing the risk of the dead­ly dis­ease for whom exces­sive cell divi­sion is its modus operan­di: can­cer3.

Luck­i­ly, not all researchers aban­doned telom­erase as a poten­tial ther­a­py. In the last ten or fif­teen years, sci­en­tists have shown that it can extend the lives of mice if cou­pled with mea­sures to reduce the risk of can­cer, or if used inter­mit­tent­ly rather than acti­vat­ed con­tin­u­ous­ly as it was in ear­ly experiments.

The next step will be to try some of these ideas in humans4.

2. Senolytic treatments: killing aged cells

As we grow grey and wrin­kled on the out­side, so too the cells that make up our insides grow old. As we age, some of our cells become ‘senes­cent’ — the sci­en­tif­ic word for aged — and, in doing so, they can accel­er­ate the age­ing of the rest of our body too. We now under­stand that senes­cent cells aren’t just benign bystanders in the age­ing process, the cel­lu­lar equiv­a­lent of can­dles on a birth­day cake, but emit a tox­ic cock­tail of mol­e­cules which can increase the risk of heart dis­ease, can­cer, cog­ni­tive decline, and much more besides.

The good news is, it might not have to be this way. Sci­en­tists have come up with a num­ber of dif­fer­ent ways to kill these cells, while leav­ing the rest of the cells in the body intact. The idea fur­thest along in devel­op­ment is ‘senolyt­ic’ drugs, the first of which were dis­cov­ered in 20155, and sev­er­al of which are already in human clin­i­cal trials.

A 2018 study6 showed the wide-rang­ing effects of giv­ing senolyt­ics to old mice: the ani­mals lived longer, which is a good start, but they also lived younger, with less chance of dis­ease, less frailty (mea­sured by per­for­mance on tiny mouse-sized gym equip­ment, from tread­mills, to tightropes, to wires to hang from), improved cog­ni­tion, and even bet­ter fur! This sug­gests that senes­cent cells aren’t just respon­si­ble for a sin­gle aspect of age­ing, but have effects on many or even all of its facets—meaning that remov­ing them could have wide­spread pre­ven­ta­tive med­i­cines for many dif­fer­ent diseases.

There are cur­rent­ly over two dozen com­pa­nies aim­ing to com­mer­cialise senolyt­ic treat­ments7, from drugs, to chem­i­cals called pep­tides, to encour­ag­ing our immune sys­tems to clear up these aber­rant cells. This diver­si­ty means we’ve got a lot of options in case some approach­es don’t work out—and means that senolyt­ics are a strong con­tender for our first true anti-age­ing treatment.

3. Cellular reprogramming: turning back the biological clock

Its name makes it sound like sci­ence fic­tion — and, once you hear what it actu­al­ly entails, it only sounds more­so — but cel­lu­lar repro­gram­ming is prob­a­bly the hottest idea in age­ing biol­o­gy right now, with enor­mous poten­tial to improve our health. The ques­tion is, do we know enough to get it from sci­ence fact in the lab, to work­able med­ical tech­nol­o­gy in the real world?

The tech­nique was first dis­cov­ered in the mid-2000s8, when Japan­ese sci­en­tist Shinya Yamana­ka was try­ing to work out what enables cells in the embryo to grow up into any kind of cell in the body, from heart, to skin, to brain. He found that a com­bi­na­tion of just four genes, now known as the ‘Yamana­ka fac­tors’, was enough to revert any cell in the body to this ‘pluripo­tent’ state, mean­ing that they could turn into any type of adult cell. I could take a skin cell from your arm, use these genes to turn it into a pluripo­tent stem cell, and then ‘dif­fer­en­ti­ate’ that stem cell into any kind of cell I liked.

Yamana­ka received the Nobel Prize in 2012 for this dis­cov­ery, and it was around this time that we realised quite how exten­sive­ly this process of induc­ing pluripo­ten­cy turns back the clock in cells. Not only does it wind back the devel­op­men­tal clock, revert­ing the cell to a pluripo­tent state, but it also seems to reduce the bio­log­i­cal age of the cells, mak­ing them younger and health­i­er in a num­ber of dif­fer­ent ways.

Turn­ing all our cells into stem cells would be a ter­ri­ble idea — I’m quite fond of my brain cells being brain cells, thanks very much — but the good news is, if you acti­vate the Yamana­ka fac­tors inter­mit­tent­ly rather than con­tin­u­ous­ly, a cell can shed a few years of bio­log­i­cal age with­out turn­ing into a dif­fer­ent kind of cell9. Doing exact­ly this has been shown to improve the health of mice with a dis­ease that caus­es them to age pre­ma­ture­ly, and regen­er­ate tis­sues in adult mice that would nor­mal­ly only heal prop­er­ly before birth, not in an adult mouse.

The promise of this approach made head­lines when bil­lion­aires includ­ing Ama­zon founder Jeff Bezos cre­at­ed a $3bn start­up called Altos Labs10 and recruit­ed a num­ber of the top sci­en­tists work­ing on repro­gram­ming, includ­ing Yamana­ka, to work on turn­ing this idea from great news for mice, to great news for peo­ple. The ques­tion is whether we can move this from a phe­nom­e­non observed in genet­i­cal­ly mod­i­fied mice in the lab to us unmod­i­fied humans walk­ing around in the wild—and $3bn may just be enough to find out.

1C. López-Otín, M. A. Blas­co, L. Par­tridge, M. Ser­ra­no, G. Kroe­mer, The hall­marks of aging. Cell. 153, 1194–1217 (2013)
2M. Kimu­ra et al., Telom­ere length and mor­tal­i­ty: a study of leuko­cytes in elder­ly Dan­ish twins. Am. J. Epi­demi­ol. 167, 799–806 (2008)
3S. E. Artan­di et al., Con­sti­tu­tive telom­erase expres­sion pro­motes mam­ma­ry car­ci­no­mas in aging mice. Proc. Natl. Acad. Sci. U. S. A. 99, 8191–8196 (2002)
4Researchers cure lung fibro­sis in mice with a sin­gle gene ther­a­py – Lifes​pan​.io
5Y. Zhu, et al., The Achilles’ heel of senes­cent cells: from tran­scrip­tome to senolyt­ic drugs. Aging Cell 14, 644–658 (2015)
6M. Xu, et al., Senolyt­ics improve phys­i­cal func­tion and increase lifes­pan in old age. Nat. Med. (2018) DOI:10.1038/s41591-018‑0092‑9.
7E. Dol­gin, Send in the senolyt­ics. Nat. Biotech­nol. (2020) DOI:10.1038/s41587-020–00750‑1
8K. Taka­hashi, S. Yamana­ka, Induc­tion of pluripo­tent stem cells from mouse embry­on­ic and adult fibrob­last cul­tures by defined fac­tors. Cell. 126, 663–676 (2006).
9A. Ocam­po et al., In Vivo Ame­lio­ra­tion of Age-Asso­ci­at­ed Hall­marks by Par­tial Repro­gram­ming, Cell 167, 1719–1733.e12 (2016)
10Meet Altos Labs, Sil­i­con Valley’s lat­est wild bet on liv­ing for­ev­er – Tech­nol­o­gy review

Contributors

Andrew Steele

Andrew Steele

PhD in physics from the University of Oxford, Science Writer and Columnist at Polytechnique Insights

After a PhD in physics from the University of Oxford, Andrew Steele decided that ageing was the single most important scientific challenge of our time, and switched fields to computational biology. After five years using machine learning to investigate DNA and NHS medical records, he is now a full-time writer, author of Ageless: The new science of getting older without getting old, presenter and campaigner.