91 MeDicIne TO why cant we live CVn << BYTHOMASKIRKWOOD >> As we grow old, our own cells begin to betray us. By unraveling the mysteries of aging, scientists may be able to make our lives longer and healthier [KEY CONCEPTS J 1 The average lifespan of humans continues to lengthen, and some cien- tists have begun to ponder whether tis trend wll cominue indefinitely 1 Notevery species ages, and some research suggests that drugs or changes in diet ‘may slow metabolism or alter basic aging processes so that we ca liv longer Allproposed longevity strategies remain unproved, however —the Editors AQ screuriric amenican | IF YOU WERE GIVEN a free hand to plan how your life will end—your last weeks, days, hours and min- ‘utes—what would you choose? Would you, for exam- ple, want to remain in great shape right up until the last minute and then go quickly? Many people say they would choose that option, but see an imnporvant catch. Ifyou are feling fine one moment, the very last thing you would want sto drop dead the next. Aad for your loving family and friends, who would sufferinsant beravement, your sudden death would bea cr- ¢lloss. On the other hand, coping with along, drawn-out terminal illness is not grat ether, nor isthe nightmare of losing a loved one inco the dark wastes of dementia. ‘We all prefer to avoid thinking about the end of life. Yet ic {is healthy to ask such questions, at least sometimes, for ourselves and to correctly define the goals of medical policy and research. Ttis | September 2010also important to ask just how far science can help in efforts tocheat death. WE'RE LIVING LONGER 1£ 1S OFTEN SAID that our ancestors had an easier relationship ‘ith death, if only because they saw it so much more often. Just 400 years ago life expectancy was shorter by around 25 years in the West, This literal fact of life resulted because so many chil- tren and young adults perished prematurely from a whole vari- cty of causes. A quarter of children died of infection before cheir fifth biethday; young women frequently succumbed to complica- tions of childbicths and even a young gardener, scratching his, hand on a thorn, might be los to fatal blood poisoning, ‘Over the course of the past century sanitation and medical care so deamatically reduced death rates in the early and middle years oflfe that most people now pass away much later, and the popu fation as a whole is older than ever before, Life expectancy isstill increasing workdwide, Inthe richer countries around the world it lengthens fve hours or more every day, and in many developing, countries that are catching up the rate quicken still faster. Today [LONGEVITY METER | the dominantcause of death isthe aging process itselfand the var- jous diseases to whic it gives rise—whether cancer, which drives cells to proliferate out of control, or Alzheimer’s, atthe opposite pole, which causes premature death of brain eels ‘Until as recently as 1990, demographers predicted confident ly thatthe historical trend of increasing life expectancy would soon cease. Aging, many researchers believed, was fixed—a pro- cess progeammed into our biology that resulted ina built-in time cof death, : ‘No one foresaw the continued inerease in life expectancy. It hhas taken our politicians and planners by surprise. Scientists are still coming to terms with che notion that aging is not fixed, that average fe spans have not reached a limit. They change and con~ tinue to change, stretched for reasons that we do not fully under- stand. The declining death rates of che very old are now driving human life expectancy into uncharted tesrtory. Ifthe prevailing certainties about homan aging have crumbled, whats eft? What docs science actually know about the aging process? "Accepting new ideas is noc always easy, because scientists are tbumans, too, and we have all grown up with fairly rigid precon- HOW MUCH MORE CAN LIFE SPAN INCREASE? Human if expectancy, or average ie span has been ising for more than 1O0yets inthe US. andglobaly (graph Evidence Lives Ger LonceR Adsareesinmedcne 2070 arragelieegeeang eo suogest however, tht bilgi constraints keep mostspe- Senna at i eiemaayasingagetnesspetcttatspedes eb Abelian gg iS Investigatrstopeintenentonsaimedatcelaingsucheon- sudttewer sd Stains illertend today’s maximum achievable fe span or Tr vrage Fron villa easthalp peeplestay heathy longer than hey do now. BUTLIMITS EXIST: The maximum age a specs, incudng hams, con ech depends on oth logy tpl organs cat each etuslear ages tat roe compe cresties aml and eon Har rcpmaundngs eat evoutenoapisveradoction ast aging andar death). “¥ MAXIMUM RECORDED LIFE SPAMS (YEARS, INLD) Qe) ene ae Mafia ro years AA: scienTIFIC AMERICANceptions abouthow the body ages. Some years ago, while driving with my family in Afriea, a goat ran under the wheels of our ve- hile and was killed instantly. When I explained to my sbeyear- cold daughter whatjust happened, sheasked, “Wasita young goat coran old goat?" Iwas curious why she wanted to know. “Ifitwas old snot as sad, because it woulda’e have had so long to live anyways" came her answer. was impressed. If such sophisticated arttudes to death form this eal, small wonder that modern sci- ence struggles to comeo tems with the reality that most of what wwethought we knew about aging is wrong. “Tocxplore current thinking about what controls aging, let us begin by imagining a body a the very endoflife. The last breath is taken, death cakes hold an fei over. At this moment, most ‘ofthe body's cells are sil alive. Unaware of what just happened, they carry our, tothe best of their abilities the metabolic Func- tions that suppor life procuring oxygen and nutrients from the surrounding environment and using them to generate the energy needed to make and power the activities of proteins (the main ‘working parts of cells) and other cellular components. Ina shorewhile,staved ofoxygen,thecells wil die, With theie tcl sngseere > patuay nda y te HEALING THE AILING CELL: New waysof slowing agin willeome ‘ram earning no to msnipulat damagodcels, sun caleen commit ‘Aide apocts called opeptoss. Of fang that, they ay begin to ‘eplate uncon and become cancerous arene a senescent state Inui ey felon But ot plat lack paths) In aor, ese ‘ngdamoped cel am apoptass oF am senescence andinducing her ‘rejuvenation (range ots) cul proectergar om te wate fects of nue cel Investigators ate Inthe carlert stags of stg ‘eve posses, whih they hope wil esd ts nen drug eats, ‘may take a less extreme course and simply stop dividing, a fate known as replicative senescence. Fifty yearsago Leonard Hayflick, now atthe University of California San Francisco, discovered that cellstend to dividea set number oftimes—now called the Hayflick limit—and then stop. Later work showed that they often stop di- ‘riding when the caps, or telomeres, that protect the ends of chro- _mosomeserode too much. But other details ofhow cell senescence sets in remained obscure Recently, though, my colleagues and I have made an exciting, discovery. We found thateach cell has highly sophisticated molec- ular circuitry that monitors the level of damage both in its DNA and nits energy formingunits known as mitochondria. When the amount of damage passes some threshold, the cll locks itself into 4 state where ir can still perform useful functions inthe body but cannever divide again. As with apoptosis, nature's bias toward the survival of the young probably means that notall these lockdowns are strictly necessary. Bur if we are to unpick the locks and so re- store some division capacity to aged cells, without unleashing the threat af cancer, we need to understand very thoroughly jst how cell senescence works. “The demanding science noeded vo make this discovery required a mukidiscplinary team, including molecular biologists, biochem- ises, mathematicians and computer scientists, as wel as state-of the-art instruments for imaging the damagei living cells. Where such discoveries might lead we do not yet know, but itis through studies ofthis kind that we can hope to identify novel drugs able to combat age-related diseases in completely new ways and thereby “shorten the period of chronic illness experienced atthe end oflife. www.Setentificamerican.c oon Abnormal cal maty mere domoge accuses ‘esl dean ‘amecanare © seen ‘saves ‘The difficulty ofthis typeof basicresearch means that many years, pethaps decades, may pass before these drugs come to market. ‘Using the science of aging to improve the end of life represents challenge, pechaps the greatest yet to face medical science. So- lutions will aot come easily, despite the claims made by the mer- chants of immortality who assert that caloric restriction or di- ctary supplements, such as resveratrol, may allow us olive lon- get. The greatest human ingenuity will be needed to meet this challenge. I believe we can and will develop treatments targeted teasing our final years. But when the end arrives, each of us— alone—will eed to come to terms with our own mortality. Alle ‘more reason then to focus on living on making the most of the time of our lives, because no magic elixir will save us. . MORE TO EXPLORE How and Why We Age eonad Hack, Balaine Books, 1894 Understanding Ageing. Robin Holiday. Cambridge University Press, 1985, Why We age: what Science Is Discovering about the Body's Journey ‘through Life, tevenN,Austod Jon Wey nd Sons, 1998 Understanding Ageing ftom an Evolutionary Perspective. 8. Kirkwood Inoural of rteral Medicine, Vol.263, No, 2 pages 17-127, February 2008. ‘The End of Ag. Thomas Kirkwood. BBC Reith Lectures. wove bbe.co.uklradio4eith2001 (© Common on tis rice nt ww Scentiicamerican comvThetnd scientiric american, 49°