Biology of Aging

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Why, after being so exquisitely

assembled, do we fall apart so predictably? Why do we

outlive dogs, only to be

outlived by turtles? Could we catch up with them? Living to 200 is not a realistic goal for this generation, but a clearer picture

of how we grow old is already

within our reach.

F ONLY GOD HAD FOUND A more reliable messenger. Back around the beginning of time, according to east African legend, he dispatched a scaveng- ing bird knov,n as the halawaka to give us the instructions for endless self-renewal. The secret was simple. Whenever age or infirmity started creeping up on us, we were to shed our skins like tattered shirts. We would emerge with our youth and our health intact. Unfortunately the ha- lawaka got hungry during his journey,

and happened upon a snake who was eating a freshly killed wildebeest. In the bartering that ensued, the bird got a sat- isfying meal, the snake learned to molt and humankind lost its shot at immortal- ity. People have been growing old and dytrg ever since.

The mystery of aging runs almost as deep as the mystery of life. During the past century, life expectancy has nearly doubled in developed countries, thanks to improvements in nutrition, sanitation

PHOTOGRAPHS BY CHRISTOPHER GRIFFITH12 NEwswEEr{ sPEcrAL rssuE

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and medical science. Yet the potential life span of a human being has not changed significantly since the halawaka met the snake. By age 50 every one ofus, no mat- ter how fit, $'ill begin a slow decline in organ function and sensory acuity. And though some will enjoy another half cen- tury of robust health, our odds of living past 120 are virtually zero. Why, after be- ing so exquisitely assembled, do we fall apart so predictabll,? Why do we outlive dogs, only to be outlived by turtlesl And what are our prospects for catching up with them?

Until recently, all we could do rn'as guess. But as the developed v'orld's population grows grayer, scientists are bearing down on the dynamics of aging, and they're amassing crucial insights. Much of the new understanding has come from the study of rvorms, flies, mice and monkeys-species rvhose life cycles can be manipulated and observ-ed in a laboratory. Hou'exactly the findings apply to people is still a matter of conjec- ture. Could calorie restriction extend our lives by half? It would take generations to find out for sure. But the big questions of why we age-and which parts of the experience we can change-are already coming into focus.

The starkest way to see hon' time changes us (aside from hauling out an old photo album) is to compare death rates for people of different ages. In Europe and North America the annual rate among tS-year-olds is roughly .05 per- cent, or one death for er.ery 2,000 kids. Fifty-year-olds are far less likely to ride their skateboards down banisters, yet they die at 30 times that rate (1.5 percent annu- ally). The yearly death rate among 105- year-olds is 50 percent, 1,000 times that of the adolescents. The rise in mortality is due mainly to heart disease, cancer and stroke-diseases that anyone over 50 is right to worry about. But here's the rub. Eradicating these scourges would add only 15 years to U.S. life expectancy (half the gain we achieved during the 20th cen- tury), for unlike children spared of small- pox, octogenarians without cancer soon die of something else. As the biologist Leonard Hal.flick observes, u-hat ulti- mately does us in is not disease per se, but our declining abiliry to resist it.

Biologists once regarded senescence as nature's way of pushing one generation aside to make way for the next. But under natural conditions, virtually no creature lives long enough to experience decrepi- tude. Our own ancestors $pically starved, froze or got eaten long before they reached

16 NEws\r/EEK sPEcIAL Issu!l

old age. As a result, the genes that leave us r'.ulnerable to chronic illness in later life rarely had adverse consequences. As long as they didn't hinder reproduction, natural selection had no occasion to rveed them out. Natural selection may even fauor a gene that causes cancer late in life if it makes 1,oung adults more fertile.

But rvhy should "later life" mean 50 in- stead of 150? Try thinking of the body as a vehicle, designed by a group of genes to transport them through time. You might expect durable bodies to have an inherent advantage. But if a mouse is sure to be- come a cat's dinner within five years, a

body that could last twice that long is a waste of resources. A S-year-old mouse that can produce eight litters annually will leave twice the legacy of a 1O-year-old mouse that delivers only four each year. Under those conditions, mice will evolve to live roughly five years. A sudden disap- pearance of cats may improve their odds of completing that life cycle, but it won't change their basic genetic makeup.

That is the predicament we face. Our bodies are nicely adapted to the harsh con- ditions our Stone Age ancestors faced, but often poorly adapted to the cushy ones u'e've created. There is no question that

In childhood the body is wonderfully resilient, and sound sleep supports the growth of tissues and bones. During the teenage years, hormonal changes trigger the development of sexual organs. Boys add muscle mass. Even the muscles in their voice box lengthen, causingvoices to deepen.

In girls, fat is redistributed to hips and breasts.

-:.. br-rrer br- exercising, eating --.,'.. ir\oiding cigarettes and stay- -.,-r- and mentallv acti\r. But can -::. "lh e \l)ect to extend our maxi- :c:pansi

: i:,'-:.hers have already accomplished -:-:: in lab experiments. In the :> :iudied so far, the slrrest \vay to

. ... litb span has been to cut back on :s riav bach. In studies dating

- - r the 1930s, researchers have found .recies as r,'ariecl as rats, monkeys :raker's yeast age more slo\\{y if

'n- gir-en 30 to 60 percent fetver calo- iiran they rn'ould normallv consume.

No one has attempted such a trial among humans, but some researchers have al- readv embraced the regimen themselves. Dr. Rov Walford, a 77-,vear-old patholo- gist at the University of California, Los Angeles, has surived for years on 1,200 calories a da.v and expects to be doing the same u'hen he's 120. That may be opti- mistic, but he loohs as splT as any 60- year-old in the photo he posts on the Web, and the anirnal studies suggest at least a partial explanation. Besides delay- ing death, caloric restriction seems to preserve bone mass, skin thickness, brain function and immune function, u'hile

providing superior resistance to heat, toxic chemicals ancl traumatic injury'.

Ho'rv could something so pen'erse be so good for you? Scientists once theorized that caloric restriction extended life b,v de- la,ving development, or by reducing bodv fat, or bi- slou'ing metabolic rate. None of these explanations surr.ir,-ed scrutinv, but stuclies have identified several likely mechanisms. 1'he first involves oxidation. As mitochondria (the power plants in our cells) release the energv in fr-rod, they gen- erate corrosive, unpaired electrons knorm as free radicals. B)' reacting n'ith nearbv fats, proteins and nucleic acids, these tinv terrorists foster eventhing from cataracts to vascular disease. It appears that caloric restriction not only slorvs the production of free radicals but helps the bod,v colrnter them more efiicientl,v.

Food restriction may also shield tissues from the damaging effects of glucose, the sugar that enters our bloodstreams u'hen $'e eat carbohvdrates. Idealll-, our bodies respond to any rise in blood glucose by releasing insulin, u'hich shuttles the sugar into fat and muscle cells for stor- age. But age or obesity can make our cells resistant to insulin. Ancl u,hen glucose molecules linger in the bloodstream, therr link up u'itl"r collagen and other proteins to rvreak havoc on nerves, organs and blood vessels. When rats or monheys are allou'ed to eat at rvill, their cells become less sensitive to insulin over time, just as ours do. But according to Dr. Marh Lane of the National Institute on Aging, older animals on calorie-restrictecl diets exhibit the high insulin sensitivitl', low blood glucose and robust health of l.oungsters. No one knou's r,r,'hether people's bodies u'ill respond the same n'ari But the find- ing suggests that life extension could prove as simple, or rather as complicated, as preseniing the insulin response.

Another possible approach is to ma- nipulate hormones. No one has shorvn conclusivelV that anSr of these substances can alter life span, but there are plenty of tantalizing hints. Consider human gro\\.th hormone, a pituitary protein that helps drive our ph-ysical development. Enthusiasts tout the prescription-only svnthetic version as an antidote to all as- pects of aging, but mounting evidence suggests that it could make the clock tick faster. The first indication came in the mid-1980s, u.hen phvsiologist Andrzej Barthe outfitted lab mice u.ith human or bovine genes for growth hormone. These mightv mice grerv to br.ice the size of normal ones, but they aged earl,v and died young. Bartke, nou. based at Southern

In manyways, the 20s are the prime oflife. We're blessedwith an efficient metabolism, strong loones and good f lexi loility. As early as the 3 0 s, however, metabolism begins to slow and women's hormone levels staftto dip. Bones mav startto lose densitv in peoplewho don't exercise orwho don't get the vitamin D required for calcium absorption.

NEwsw!rEK sPECIAL IssTTE 1l

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Illinois Universilv, witnessed something very different in 1996, when he began studying a strain of rodents called Ames dwarf mice. Due to a congenital lack of growth hormone, these creatures reach only a third the size of normal mice. But they live 5O to 6o percent longer.

As it happens, the mini-mice aren't the only ones carrying this auspicious gene. The island of Krk, a Croatian outpost in the eastern Adriatic, is home to a group of people who harbor essentially the same mutation. The "little people of Krk" reach an adult height ofjust four feet five inch- es. But like the mini-mice, they're excep- tionally long-lived. Bartke's mouse stud- ies suggest that besides stifling growth hormone, the gene that causes this stunt- ing may also improve sensitivity to-you guessed it-insulin. If so, the mini-mice, the Croatian dwarles and the half- starved rats and monkeys have more than their longevity in common. No one is suggesting that we stunt people's growth in the hope of extending their lives. But if you've been pestering your doctor for a vial of growth hormone, you may want to reconsider.

Growth hormone is just one of several that decline as we age. The sex hormones

Around 40, people often staft noticing gray hairs, mild memory lapses and difficulty focusing their eyes on small t1pe. Around 5 1, most women will experience menopause. Estrogen levels plummet, making the skin thinner and bones less dense. Men suffer more heart disease than women at this age. Metabolismslows downinboth sexes.

estrogen and testosterone follow the same pattern, and replacing them can re- iuvenate skin, bone and muscle. But like growth hormone, these tonics can have costs as well as benefits. They evolved not to make us more durable but to make us more fertile. As the British biologist Roger Gosden observed in his 1996 book, "Cheating Time," "sex hormones are re- quired for fertility and for making biolog- ical gender distinctions, but they do not prolong life. On the contrary a price mav have to be paid for living as a sexual be- ing." Anyone suffering from breast or prostate cancer would surely agree.

In most of the species biologists have

studied, fertility and longevity have a see- saw relationship, each rising as the other declines. Bodies designed for ma-rimum fertility have fewer resources for self- repair, some perishing as soon as they re- produce (thinh of spawning salmon). By contrast, those with ertraordinary life spans are tlpically slow to bear offspring. Do these rules apply to people? The evi- dence is sketchy but provocative. In a 1998 study, researchers at the Universig' of Manchester analyzed genealogical records of 32,ooo British aristocrats born during the 1,135-year period between 740 and 1875 (long before modern contracep- tives). Among men and women who

made it to 60, the least fertile u'ere the most likely to sundve beyond that age. A u'hopping 50 percent of the rvomen u'ho reached 81 u.ere childless.

Eunuchs seem to enjoy (if that's the u'ord) a similar advantage in longevity. During the 1940s and 5Os, anatomist James Hamilton studied a group of men- tally handicapped men lr.ho had been cas- trated at a state institution in Kansas. Life expectancy $,?s just 56 in this institution, but the neutered men lived to an average age of 69-a 23 percent advantage-and not one of them went bald. No one l<nows exactly how testosterone speeds aging, but athletes u,'ho abuse it are prone to ail- ments ranging from hlpertension to kid- ney failure.

All of this research holds a fairly obvi- ous lesson. Life itself is lethal. and the things that make it sweet make it more lethal. Chances are that by starving and castrating ourselves, we really could se- cure some extra vears. But most of us would gladly trade a lonely decade of stubborn sun'ival for a richer middle age. Our bodies are designed to last only so long. But with care and maintenance, they'll live out their u'arranties in style.

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life expectancy has risen dramatically, from 47 years in 1900 to 77 years in 1998. Here's a look at the progress we've made and the problems that remain.

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20 NEwswEEK sPECIAL ISSUtI

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N-U\VS\\rEEK SPECIT\t ISSUE 21