Editorial

A Divide-and-Conquer Assault on Aging:Mainstream at Last

Aubrey D.N.J. de Grey

‘‘Separa et impera’’—Sir Francis Bacon in a letter to James I

Iconsidered writing this as a ‘‘Commentary’’ article,because that is ultimately what it is, but it is just too im-

portant for that, so an editorial it shall be.On June 6th, a review appeared1 concerning the state of

aging research and the promising ways forward for the field.So far, so good. But this was not any old review. Here’s why:

� it appeared in Cell, one of the most influential journals inbiology;

� it is huge by Cell’s standards— 24 pages, with well over300 references;

� all its five authors are exceptionally powerful opinion-formers—senior, hugely accomplished and respectedscientists’

� above all, it presents a dissection of aging into distinct(though inter-connected) processes and recommends acorrespondingly multi-pronged (‘‘divide and con-

quer’’) approach to intervention

It will not escape those familiar with SENS that this lastfeature is not precisely original, and it may arouse someconsternation that no reference is made in the paper to thatprior work. But do I care? Well, maybe a little—but really,hardly at all. SENS is not about me, nor even about SENS ascurrently formulated (though a depressing number of com-mentators in the field persist in presuming that it is). Rather,it is about challenging a profound, entrenched, and insidiousdogma that has consumed biogerontology for the past 20years, and which this new review finally—finally!—chal-lenges (albeit somewhat diplomatically) with far more au-thority than I could ever muster.

The above is a pretty dramatic characterization, I realize,so I will not cut too many corners in defending it. I appre-ciate that readers will vary in their familiarity with the rel-evant history of the field, so I shall start from the beginning.

Let’s step back 30 years, to well before my time. In theearly 1980s, biogerontology was a backwater in biology,disrespected for its ‘‘descriptive’’ nature, i.e., for its paucity ofopportunity for hypothesis-driven work. This makes nosense to me—it stands to reason that any field must start out

as descriptive, and that the scientists who piece togetherenough of the puzzle to enable a progressive transition tomore hypothesis-driven work are every bit as important andworthy of praise as those who come after them—but it is adocumented and undisputed fact. But also biogerontologywas a conceptually fragmented discipline. Over the preced-ing decades, starting in the 1950s with Denham Harman’s freeradical theory and continuing right up to the early 1980s withthe introduction of glycation and epigenetic noise as potentialplayers, a positive zoo of ‘‘theories of aging’’ had emerged—and that’s even if you count only the mechanistic ones, whichat the end of the day are those that matter when consideringstrategies for intervention. This led to a view that aging is achaotic, un-selected, un-programmed phenomenon—and togreat despondency in the field with regard to any prospect forever doing anything about it. (That despondency fueled anincreasing tendency to claim, at least in the presence of anyonewith deep pockets, that intervention was not even a main goalof the field—but I digress, and will do so no further, not leastbecause my views on such matters have already been aired adnauseam in this space and elsewhere.)

In parallel with all this, however, another strand of bio-gerontology was moving forward—the study of calorie re-striction (CR). CR had been known since the 1930s to extendrodent longevity by 30%–50%, and had inevitably been thefocus of intense study. But attempts to dovetail it with‘‘theories of aging’’ had been thoroughly unsuccessful; in thewords of the pioneering CR researcher Roy Walford, CRsupported every theory of aging.

Into this morass, in 1983, came Michael Klass’s discoveryof a Caenorhabditis elegans mutant that greatly increasedlongevity.2 Huh???? How could such a mutant exist? Sinceaging is chaotic, surely it was impossible to slow it downin toto (as was clearly required to extend life span much) bydisrupting just one gene. Indeed, despite increasingly clearfollow-up work, it was not for another decade (until CynthiaKenyon’s discovery of a different mutation with an evenbigger effect3) that this advance was given real credence andconsideration.

SENS Research Foundation, Mountain View, California.

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Those new to this timeline may think that the next step isobvious: That these mutations are ways to get to the bottomof the tension between the chaotic nature of aging revealedby mechanistic work and the unitary nature revealed by CR.And indeed they are—and rather blatantly so, because bothKlass’s and Kenyon’s mutants were in genes involved in thedauer pathway, the alternative developmental strategyadopted by C. elegans larvae when deprived of adequatenutrients. But that’s not what happened.

What actually happened, once Kenyon’s contributionmade it unequivocal that aging could be modulated bygenes, was that large numbers of ambitious (and talented,sure) biologists flocked to biogerontology, attracted by theseductive combination of public interest and new-foundtractability to the fashionable cell and molecular biologytechniques at which they were already expert. A positivetorrent of publications in the highest-impact journals dulyensued and still shows no sign of diminishing. But thesepublications were, necessarily, focused on manipulationsand dissections of precisely those aspects of aging that werethe most amenable to such intervention. It was virtuallyforgotten, at least if the highest-impact journals were any-thing to go by, that that might not be the whole story.

I am not disputing that to some extent, a rising tide floatsall boats. But only to some extent. As an example, considerthe role of telomere shortening in aging—something onwhich those familiar with my work will know I harbordoubts, but that isn’t the point here. It was back in 1997 thattelomerase knockout mice were shown to have undimin-ished life span at first, but there were various problems aftera few generations of inbreeding, problems that could beclearly linked to failed maintenance of stem cells in rapidlyrenewing tissues.4 The single most obvious, but somewhatexpensive, next experiment was to generate a mouse with aknockout of endogenous telomerase but a drug-inducibletransgenic copy so that telomerase could be reactivated latein life, thereby determining which aspects of telomere-induced aging could be reversed by re-lengthening of telo-meres. And this experiment was indeed done. But was itdone at once? Not as such: It took FOURTEEN YEARS beforesuch work saw the light of day.5 I confess I have not con-sulted Ron DePinho to determine how hard he tried to obtainfunding for such work at earlier times, but I think you cansee my point.

It has been blindingly obvious for the past decade, and notonly to me, that there is actually no data conflict here. CR is asimple intervention, and aging is complex and chaotic. Thatdoesn’t pose a paradox: It just says that CR triggers a pro-grammed response that fans out into a bunch of processeswith the combined effect of slowing aging. It’s easy to comeup with plausible evolutionary advantages for the posses-sion of such a response, so its existence is not paradoxical.But what does it mean for biomedical intervention?

Two decades–long studies of CR in monkeys have re-ported results in recent years,6,7 and although many com-mentators have over-simplistically favored one over theother, the studies actually tell a broadly similar story: Toomuch refined food is really bad for you, but severe restrictionof natural food is not measurably better for you (at least notif you’re at least averagely healthy for your age to beginwith) than slight restriction. Because monkeys are so similar

to humans, this is strong evidence that both CR itself(however performed, e.g., by intermittent fasting) and CRmimetics (drugs that seek to trick the body into thinking it’son CR even when it isn’t) will be minimally if at all effectiveagainst aging in humans.

We may summarize the foregoing as follows. Aging hasbeen shown, over several decades, to consist of a multiplicityof loosely linked processes, implying that robust postpone-ment of age-related ill-health requires a divide-and-conquerapproach consisting of a panel of interventions. Because suchan approach is really difficult to implement, gerontologistsinitially adopted a position of such extreme pessimism thatall talk of intervention became unfashionable. The discoveryof genetic and pharmacological ways to mimic CR, after abrief period of confused disbelief, was so seductive as away to raise the field’s profile that it was uncritically em-braced as the fulcrum of translational gerontology for 20years, but finally that particular emperor has been decisivelyshown to have no biomedically relevant clothes. The publi-cation of so authoritative a commentary adopting the‘‘paleogerontological’’ position, that aging is indeed chaoticand complex and intervention will indeed require a panel oftherapies, but now combined with evidence-based optimismas to the prospects for implementing such a panel, is a keystep in the elevation of translational gerontology to a trulymature field.

References

1. Lopez-Otın C, Blasco MA, Partridge L, Serrano M, KroemerG. The hallmarks of aging. Cell 2013;153:1194–1217.

2. Klass MR. A method for the isolation of longevity mutants inthe nematode Caenorhabditis elegans and initial results. MechAgeing Dev 1983;22:279–286.

3. Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R. A C.elegans mutant that lives twice as long as wild type. Nature1993;366:461–464.

4. Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM,DePinho RA, Greider CW. Telomere shortening and tumorformation by mouse cells lacking telomerase RNA. Cell1997;91:25–34.

5. Jaskelioff M, Muller FL, Paik JH, Thomas E, Jiang S, AdamsAC, Sahin E, Kost-Alimova M, Protopopov A, Cadinanos J,Horner JW, Maratos-Flier E, DePinho RA. Telomerase re-activation reverses tissue degeneration in aged telomerase-deficient mice. Nature 2011;469:102–106.

6. Colman RJ, Anderson RM, Johnson SC, Kastman EK, KosmatkaKJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, KemnitzJW, Weindruch R. Caloric restriction delays disease onset andmortality in rhesus monkeys. Science 2009;325:201–204.

7. Mattison JA, Roth GS, Beasley TM, Tilmont EM, Handy AM,Herbert RL, Longo DL, Allison DB, Young JE, Bryant M,Barnard D, Ward WF, Qi W, Ingram DK, de Cabo R. Impactof caloric restriction on health and survival in rhesus mon-keys from the NIA study. Nature 2012;489:318–321.

Address correspondence to:Aubrey D.N.J. de Grey

SENS Research FoundationMountain View, CA

E-mail: aubrey@sens.org

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