book winter 2006 - american academy of arts and sciences...susan green½eld, david a. hollinger,...

coming up in Dædalus:

Chris Wilson The century ahead 5Henry J. Aaron Longer life spans: boon or burden? 9Sarah Harper Mature societies 20Paul B. Baltes Human dignity & the limits of life 32Linda Partridge Of worms, mice & men 40Hillard Kaplan The life course of a foraging species 48Dennis J. Selkoe Deciphering Alzheimer’s disease 58Caleb E. Finch Aging, inflammation & the body electric 68Kenneth Clark The artist grows old 77Jagadeesh Gokhale& Kent Smetters Social Security & the aging of America 91

Lisa F. Berkman& M. Maria Glymour How society shapes life spans 105

Charles Wright Last Supper 115

Ree Davis I kneel before you 116

Daniel Bell & Wolf Lepenies on society & sociology past & present 120

Jeri Laber on torture 124

Robert F. Nagel on the decline of federalism 127

on compromised work, poetry for nonpoets &c. 131

DædalusJournal of the American Academy of Arts & Sciences

Winter 2006

onaging

poetry

½ction

dialogue

notes

letters

Dæ

dalusW

inter 200

6: on aging

U.S. $13; www.amacad.org

plus poetry by Peg Boyers, Kevin Carrizo di Camillo, John Kinsella,Charles Simic, Lawrence Dugan &c.; ½ction by Adam Braver, DorianGossy &c.; and notes by Michael Cook, Norbert Schwarz, Joel F.Handler, William B. Quandt, William Galston, Richard Morris,Robert J. Sharer &c.

Patricia Meyer Spacks, Steven Marcus, Andrew Delbanco,Pauline Yu, Gerald Early, Anthony Grafton, Thomas Crow, JackBalkin & Sanford Levinson, and Dag½nn Follesdal & Michael L.Friedman

on the humanities

Antonio & Hanna Damasio, Jerry Fodor, Carol Gilligan, GeraldEdelman, Jorie Graham, Raymond Dolan, Arne Öhman, MarkJohnson, Jacques d’Amboise, and William E. Connolly

on body in mind

Akeel Bilgrami, Wendy Doniger, Amartya Sen, Stephen Greenblatt,Kwame Anthony Appiah, Sydney Shoemaker, Joseph Koerner,Susan Green½eld, David A. Hollinger, Claudio Lomnitz, CarolRovane, Todd E. Feinberg, Ian Hacking, and Courtney Jung

on identity

William H. McNeill, Adam Michnik, Jonathan Schell, James Carroll,Breyten Breytenbach, Mark Juergensmeyer, Steven LeBlanc, JamesBlight, Cindy Ness, Neil L. Whitehead, and Mia Bloom

on nonviolence& violence

FOUNDED 1780

Joan Roughgarden, Terry Castle, Steven Marcus, Claudia Goldin,Brian Charlesworth, Elizabeth Benedict, Wendy Doniger, LawrenceCohen, Anne Fausto-Sterling, Catharine MacKinnon, Tim Birkhead,and Margo Jefferson

on sex

Joyce Appleby, John C. Bogle, Lucian Bebchuk, Robert W. Fogel,Jerry Z. Muller, Peter Bernstein, Richard Epstein, Benjamin M.Friedman, John Dunn, and Robin Blackburn

on capitalism& democracy

Anthony Kenny, Thomas Laqueur, Shai Lavi, Lorraine Daston, PaulRabinow, Michael S. Gazzaniga, Robert George, Robert J. Richards,and others

on life

The twentieth century was, above allelse, a century of population growth; the twenty-½rst century will be a cen-tury of aging. Between 1900 and 2000the world’s population quadrupled,from around 1.5 billion to over 6 billion.Most of this increase occurred afterWorld War II. At present, it seems un-likely that the population will grow bymore than about a further 50 percent.The most plausible forecasts see a pop-ulation numbering between 9 and 10 billion by about 2050, with stability ordecline in total population thereafter.

However, the population at older ages will increase far more quickly in the coming century than in the last. In-deed, the end of population growth andits replacement by aging are logically re-lated. All rapidly growing populationsare young. If each birth cohort is largerthan the one before, there will always beplenty of young people.

Population growth was so characteris-tic of the recent past that we tend to re-gard it as the norm. However, for mostof human history the long-run rate ofpopulation growth has been very close to zero. From the biblical Adam and Eve,it would have taken only thirty-two dou-blings of the population to reach over 8billion. At the rate of population growthseen in the 1960s and early 1970s–over 2percent a year, implying a doubling timeof around thirty years–and given thatthe gap between generations is also usu-ally about thirty years, such an increasecould have taken place inside a millenni-um. Even James Ussher’s 1650 estimateof October 23, 4004 b.c. as the date ofcreation implies we have been aroundmuch longer than that. And since Homosapiens actually emerged one hundredand ½fty thousand or so years ago, therate of growth has obviously been closeto zero.

Similarly, extrapolating the growthrates of the recent past into the futuresoon yields logically impossible ½gures.Ansley Coale once calculated that agrowth rate of 2 percent a year sustainedfor ½ve thousand years would lead to thesheer volume of human beings exceed-ing that of the solar system.

The absence of growth is a necessarybut not suf½cient condition for aging;

Dædalus Winter 2006 5

Chris Wilson

The century ahead

Chris Wilson is a staff member of the World Pop-ulation Program at the International Institute forApplied Systems Analysis in Laxenberg, Austria.One of Europe’s most widely cited demographers,he is currently researching the causes and conse-quences of global demographic convergence.

© 2006 by the American Academy of Arts & Sciences

we also need long life expectancy. Inpopulations before the modern medi-cal era, relatively few people survived to reach three score years and ten. Thus,population aging is a novelty requiringboth long lives and a low growth rate(i.e., low fertility). Though rare in thepast, these conditions are now becomingthe norm around the world.

When demographers try to under-stand the determinants of aging, theyuse one of social science’s great general-izing models: the demographic transi-tion. When a population modernizes, it undergoes, along with many otheraspects of development, a set of inter-connected changes called the demo-graphic transition. According to thismodel, every population at some pointhas high fertility (mostly between fourand six children per woman) and low life expectancy (mostly between twenty-½ve and forty years). With the spread of modern medicine and public health,mortality improves; as family planningand contraceptive use become the norm,fertility falls. Usually life expectancyrises ½rst, with a delay before fertilitydeclines. This difference in timing leadsto substantial population growth beforethe two processes come back into bal-ance.

This process of transition began in thelate eighteenth and nineteenth centuriesin Europe, the United States, and theother neo-Europes; it became a globalphenomenon after World War II. Today,more than half of the world’s people livein places where fertility is at or belowthe level needed for long-run intergener-ational replacement (about 2.1 childrenper woman), and global life expectancyis approaching seventy years.

Trends in mortality can be followed inconsiderable detail for many Europeancountries from the mid-nineteenth cen-

tury, and for a few especially well-doc-umented cases, as far back as the late1700s. For Japan and the United Statesdetailed information dates back to theearly twentieth century. What these sta-tistics reveal is both simple and striking.There has been an enormous reductionin mortality, with life expectancy for thetwo sexes combined now approaching,or even exceeding, eighty in most devel-oped countries. Even more remarkably,this progress has been very regular formany decades. Jim Oeppen and JamesVaupel have shown, for example, thatthe trend in “best-practice” life expec-tancy (i.e., the country with the lon-gest life expectancy in each year) hasbeen linear for more than 150 years.1In each decade the “state of the art” hasincreased about 2.5 years. Moreover, al-though there has been some variation atthe national level, most developed coun-tries have demonstrated strongly lineartrends in life expectancy for the whole ofthe twentieth century.

Paradoxically, although this trend hasbeen evident in mortality statistics formany decades, it is only in the last fewyears that it has been recognized. De-mographers, actuaries, and others con-cerned with forecasting mortality hadalways hitherto assumed that life expec-tancy was approaching some asymptot-ic limit and would thus level off in thenear future. But if there is some biologi-cal limit to extending longevity, there isno sign of it yet. As Oeppen and Vaupelpoint out, estimates of the maximumpossible life expectancy made through-out the twentieth century were, on aver-age, surpassed within ½ve years of beingmade. This consistent error is of morethan purely academic interest–pension-

6 Dædalus Winter 2006

ChrisWilson on aging

1 Jim Oeppen and James W. Vaupel, “BrokenLimits to Life Expectancy,” Science 296 (2002):1030–1031.

and health-care systems have been fund-ed on the basis of large underestimatesof the number of elderly people in thefuture.

The linearity of the upward climb inlife expectancy has occurred in spite ofthe fact that very different age groupsand causes of death have been involvedin different eras. Before World War II,almost all progress took place in reduc-ing infectious diseases, with the biggestimpact for infants and children. In con-trast, today much of the improvement is concentrated at old ages. Perhaps the best analogy for these remarkablechanges is to be found in models of eco-nomic growth. Just as modern theoryhypothesizes the existence of an endoge-nous rate of growth that is in some sensebuilt into our economic system, so toothere may be an endogenous rate of im-provement in health, as measured by lifeexpectancy. In any event, we have everyreason to expect that continued increas-es in the average length of life will aug-ment population aging.

There are, of course, exceptions to thisoptimistic picture. In the Soviet Unionand its client states in Eastern and Cen-tral Europe, life expectancy stagnatedfrom the 1960s until the end of Com-munism. It then worsened still further in many cases, in the immediate after-math of revolution. In Russia and manyof the post-Soviet states it remains low,especially for men. Male life expectan-cy in Russia today is roughly the same as it was in 1950: about sixty years. Toput this stagnation into perspective, theequivalent ½gure for the United Stateshas increased since 1950 by almost tenyears from sixty-six to seventy-six.

In the post-Communist countries fur-ther west, however, the last decade hasseen rapid improvements; life expec-tancy there will likely converge to levelsseen in Western Europe within a few de-

cades. The origins of the health crisisunder Communism and its persistencein Russia, Ukraine, and the other post-Soviet states is a matter of heated de-bate in both the scienti½c and general literature. Whatever the cause, the cri-sis serves as a warning against unqual-i½ed Panglossian optimism. Likewise,the emergence of hiv/aids and theassociated reemergence of tuberculosismake clear that all future estimates ofimprovement in public health must takeinto account the potential for severe re-versals.

Overall, however, the last half-centu-ry has seen unprecedented convergencein mortality patterns around the world.While rich countries still lead in lifeexpectancy, the gap between these lead-ers and most developing countries hasshrunk substantially. In fact, there hasbeen more convergence in demographythan in any other aspect of moderniza-tion. For example, consider Latin Amer-ica as a whole, where the United Nationsestimates current life expectancy is sev-enty-two years, and gdp per head (ad-justed for inflation and other factors) is below $4,000, according to the Orga-nization for Economic Cooperation andDevelopment. Now consider the UnitedStates. Life expectancy in the UnitedStates was seventy-two years as recent-ly as the early 1970s. In contrast, the U.S.gdp per head exceeded $4,000 by 1900.Latin America is a century behind theUnited States in income growth, but on-ly thirty to thirty-½ve years behind in lifeexpectancy. We can make similar com-parisons for most developing countries.And though the gaps in educational at-tainment or urbanization are somewhatsmaller than in gdp per head, none ofthe other conventional quantitative in-dices of development has converged asrapidly as demography.


The centuryahead

In recent decades there has also been astriking convergence in fertility, whichhas declined rapidly in most countries.More than half of the world’s popula-tion now lives in countries or regions inwhich fertility is below the level neededfor intergenerational replacement.2 Inmost of Southern Europe (includingItaly and Spain) and in most of Centraland Eastern Europe, the total fertilityrate (the number of children born perwoman) is below 1.3. Similar values arenow seen in Japan, South Korea, andmany of the more developed parts ofChina. Even some countries that mightseem unlikely candidates have experi-enced rapid fertility decline. In Iran, for example, fertility fell from over sixchildren per woman to just over twobetween the mid-1980s and mid-1990s.In contrast, fertility in the United Stateshas seemed to defy gravity, staying closeto or even above the replacement levelfor the last two decades. Among the de-veloping countries in which fertility is now lower than in the United States areChina, Brazil, Thailand, and Tunisia. Ifthe trends of the last twenty-½ve yearscontinue for another decade or so, theU.S. fertility level will be well above themedian for the human population as awhole.

The very speed of fertility decline inmany countries will produce an exagger-ated form of aging. While aging is an in-evitable and global phenomenon, coun-tries in which fertility has fallen rapidlywill experience a form of ‘super aging’ in the middle decades of this century.The baby boom cohorts of SouthernEurope or the pretransition cohorts inChina are very large compared to thosethat followed, and their getting old willgreatly exacerbate any problems that ag-ing generates.

There is also a sense in which agingcan be ‘locked in’ as part of a country’sdemographic regime through a form of negative momentum. For example, in Southern Europe, the large number of baby boomers moving through thechildbearing ages has disguised the verylow fertility rate of recent decades. Thelargest age groups at present are thoseages 25 to 39. In the coming decades,however, the much smaller cohorts born since the mid-1980s will be in thereproductive ages. Unless these cohorts(currently ages 0 to 19) have much high-er fertility than their parents, the num-ber of births in countries such as Italyand Spain will shrink even more rapid-ly in the future than it has so far. In con-trast, the United States and other coun-tries in which fertility has stabilized atclose to the replacement level (in Eu-rope, they include France and the Nor-dic countries) will face much less severechallenges from demographic disrup-tion.

The future is always uncertain to some degree, but when trends have been so clear and so consistent for de-cades, they form a solid basis for pre-diction. It is very close to certain thataging will be one of the de½ning globalphenomena in the twenty-½rst centu-ry. The ways in which societies choose to adapt to this new reality will test the old adage that “demography is destiny.”Fatalism, however, is uncalled for–to a substantial degree we can still chooseour future. However, demography doesimpose strong constraints on the rangeof feasible options. Taking these con-straints into account is the basis for in-formed reactions to the challenges posedby aging.


ChrisWilson on aging

2 Chris Wilson, “Fertility Below ReplacementLevel,” Science 304 (2004): 207–209.

Aging angst’ has become a boomingindustry among scholars. For example,the ethicist Leon Kass and others arguethat, on a personal level, increasing lon-gevity may deprive life of its savor andundermine the quest to achieve. Kassstates, “If you push those [mortality]limits back, if those limits become out ofsight, we are not inclined to build cathe-drals or write the BMinor Mass, or writeShakespeare’s sonnets and things of thatsort.”1 Kass never says how much of anincrease in longevity is too much, onlythat if science were able to slow aging, it would put humankind on a slippery

slope to immortality, with all its seduc-tive and corrosive effects.

Meanwhile, on a societal level, econo-mists like Laurence Kotlikoff and ScottBurns worry that the growing percent-age of the elderly in the population por-tends economic calamity:

Let your mind wander toward the future.Move, slowly, to the year 2030 . . . . What do you see? You see a country [the Unit-ed States] whose collective population isolder than that in Florida today. You see acountry where walkers outnumber stroll-ers. You see a country with twice as manyretirees, but only 15 percent more workersto support them. You see a country withlarge numbers of impoverished elderly citizens languishing in understaffed, over-crowded, substandard nursing homes. You see a government in desperate trou-ble. It’s raising taxes sky high, drasticallycutting retirement and health bene½ts,slashing defense, education, and othercritical spending, and borrowing far be-


Henry J. Aaron

Longer life spans: boon or burden?

Henry J. Aaron is Bruce and Virginia MacLaurySenior Fellow at The Brookings Institution. Co-author of “Countdown to Reform: The GreatSocial Security Debate” (with Robert D. Reis-chauer, 2001) and “Can We Say No? The Chal-lenge of Rationing Health Care” (with MelissaCox and William B. Schwartz, 2005), he is cur-rently researching Medicare reform. He has alsowritten and coedited many volumes, including“Agenda for the Nation” (2003) and “Copingwith Methuselah: The Impact of Molecular Bi-ology on Medicine and Society” (2004). Aaronhas been a Fellow of the American Academy since1993.


1 Transcript of interview of Leon Kass by Mor-ton Kondracke, . Parts of this essaydraw on chapter 2 of Henry J. Aaron and RobertD. Reischauer, Countdown to Reform: The GreatSocial Security Debate (New York: Century Foun-dation Press, 2001). The views expressed hereare my own and do not necessarily reflect thoseof the trustees, of½cers, or staff of The Brook-ings Institution.

‘

yond its capacity to repay. It’s also print-ing tons of money to ‘meet’ its bills. Yousee major tax evasion, high and risingrates of inflation, a growing undergroundeconomy, a rapidly depreciating currency,and more people exiting than entering thecountry. They are leaving because they’resure things will get still worse.

What is going on here?The prospect of living long lives, with

physical and mental capacities intact,has long occupied the human imagina-tion. To be sure, the ability to slow orprevent the onset of serious illnesses and even aging may create risks. But the harm that may result if something is done to excess does not require forgo-ing the good that results from doing thesame thing in moderation. George Willillustrates this in his case for therapeuticcloning:

Life . . . is lived on a slippery slope: taxationcould become con½scation; police couldbecome gestapos. But the bene½ts fromtaxation and police make us willing towager that our judgment can stop slidesdown dangerous slopes.2

Warnings that a growing elderly popu-lation threatens national well-being areof a different character, but are also odd.Population aging can be delayed if birthrates remain high and the populationcontinues to expand. Until populationstabilizes, increasing longevity can coex-ist with a stable, low fraction of the pop-ulation that is elderly. Of course, unlim-ited population growth creates problemsof its own. It evokes specters of ‘stand-ing room only,’ natural resource exhaus-tion, environmental degradation, and–at least for poor nations–inescapablepoverty. Of course, population growthmust end. When it does, increased

longevity means an older population.Keynes had only half the story: in thelong run we will, indeed, all be dead, butwith rising longevity we will be old ½rst.

Despite a widespread desire to pro-long life, the human species for millen-nia made no progress toward ful½lling it. Even tiny increases in longevity sus-tained over the numberless generationsof human existence would have resultedin life spans far greater than any now ob-served. Instead, until the modern eco-nomic era, few infants lived to experi-ence what now would be called old age.

Nearly all of the current extension of life spans is a by-product of rising in-comes–the result of the Industrial Rev-olution and the science that produced it. Before the Industrial Revolution, theelderly formed a small fraction of thepopulation because people died youngand birth rates were high.3 In no Euro-pean nation did as much as 5 percent of the population reach age 65 until themiddle of the nineteenth century; innone did 10 percent of the populationreach age 65 until after 1930. Now, pro-jections indicate that by the year 2050more than 20 percent of the populationwill exceed age 65 in most developednations, and in several the proportionwill approach or exceed 30 percent.4

Visions of the United States as a na-tion of doddering codgers notwithstand-ing, the U.S. population is projected to


Henry J.Aaron on aging

2 George Will, “Column,” The Washington Post,August 4, 2005.

3 Paradoxically, famine, which reduces life ex-pectancy, could increase the proportion of thepopulation that is elderly because it also causesbirth rates to fall. For analogous reasons socould emigration of the young.

4 U.N. projections indicate that more than 35 percent of the population in Japan and Ita-ly will be over age 65. According to U.N. pro-jections, 20.9 percent of the population in theUnited States will be over age 65, the lowestproportion among developed nations.

remain among the youngest in the devel-oped world because of its relatively highbirth and immigration rates. Althoughthe proportion of the U.S. populationover age 65 will rise from 12.3 percent in2005 to 20.6 percent in 2050, the laborforce will grow, not shrink, by 29 percentover that period. In sharp contrast, theproportion of the Japanese populationover age 65 is already 19.7 percent and is projected to rise to 35.9 percent by2050. The Organization for EconomicCooperation and Development projectsthat the Japanese labor force will shrinkby more than one-third between 2005and 2050.5

So, if one embraces a dismal vision of the demographic future in the Unit-ed States, then one must tremble at thetruly unspeakable prospects confront-ing France, Germany, Japan, and Italy. In fact, it’s hard to ½gure out whereAmericans, who according to Kotlikoffand Burns will be fleeing their wreck ofa nation, would actually go. Those whosee population aging as a source of col-lective calamity need to explain why theachievement of sustained economic ad-vance and the deferral of death and ofphysical and mental decline–all age-oldgoals of human striving–is a global ca-lamity.

To be sure, extended life expectancywill pose a variety of challenges. In alldeveloped nations, public budgets bearmore of the cost of care and support forthe elderly than for children. Populationaging will therefore tend to push up taxrates. Increased longevity could also cre-

ate serious social and economic chal-lenges if the years of extended life areones of mental and physical in½rmity;but prospective medical advances prom-ise treatments and, possibly, cures forconditions that produce physical andmental decline. For the most part, theincrease in life expectancy made possi-ble by rising incomes, improved publichealth, and medical advances is a mon-umental achievement. In the UnitedStates, population aging, like the post–World War II baby boom, will doubtlessrequire some quite signi½cant economicand social adjustments, but the adjust-ments are straightforward and requireno more than honest political leader-ship.

I shall begin this survey by recallingwhat growing old meant to previousgenerations in the United States and juxtapose a realistic image of what be-coming old will mean for our childrenand grandchildren. I shall then outlinethe genuine economic problems thatincreasing longevity and populationaging will raise and the steps that will be necessary to deal with them.

A scrim of forgetfulness shields usfrom the rather ugly reality of growingold in the America of just a few genera-tions past. Let us draw back that curtainto examine what growing old meant forthe generations born in 1860, 1890, and1930.6

The 1860 cohort was born in a nationthat still treated slavery as a constitu-tional right. A quarter of those born in1860 died before turning age 20, half be-fore reaching age 65. Living conditionsand public sanitation were appalling bytoday’s standards: few houses had in-door plumbing, and few cities had mu-nicipal water and sewer systems. Sur-


Longer lifespans: boonor burden?

5 Thai Than Dang, Pablo Antolin, and HowardOxley, “Fiscal Implications of Ageing: Projec-tions of Age-Related Spending,” Organizationfor Economic Cooperation and Development,Economics Department Papers No. 305, Sep-tember 19, 2001. The Japanese labor force isprojected to decline on average by 0.9 percent-age points annually from 2000 to 2050. 6 Aaron and Reischauer, Countdown to Reform.

gery was uncommon and dangerous be-cause surgical technique was primitiveand anesthesia was dangerous. Inocula-tions were uncommon. Childhood dis-eases winnowed the young, and pneu-monia was known as the ‘widow’sfriend.’

By current standards, the 1860 cohortwas a nation of educational dropouts,although the United States led the worldin mass education. Out of every hundredstudents who started primary school,seventy ½nished, twelve completed highschool, and three graduated from col-lege. Economic growth was rapid butuneven. The U.S. economy underwentthirteen economic contractions between1885 and 1925; many were catastrophicby modern standards. Output fell 7 per-cent following the 1893 panic, 8 percentduring the 1907–1908 depression, and 6 percent on the eve of World War I.Since World War II, output has never fallen more than 3.7 percent in any re-cession.

Women gave birth to an average ofmore than ½ve children. The backbreak-ing job of caring for children, husbands,brothers, sisters, and parents in a worldwithout washing machines, vacuumcleaners, refrigerators, or dishwasherswas borne, typically by women, untildeath and lightened only as family mem-bers died or moved away. Once married,few white women worked outside thehome. Those who worked for pay al-most invariably performed menial tasks.Many women, especially African Ameri-can women, were domestics.

Old age was not a passage to a ‘newmode of living,’ but a continuation ofwhat life had been when one was young.Three-quarters of men born in 1860 andstill alive at age 65 continued to work for pay until death, disability, or eco-nomic catastrophe intervened. Such acatastrophe–the Great Depression–did

intervene when the 1860 cohort was 69-years-old. By 1932, a quarter of the workforce was unemployed. The elderly weremore likely than the young to lose theirjobs and less likely to ½nd new ones. Pro-tracted unemployment, bank failures,plunging stock prices, and collapsingreal-estate values destroyed the savingsof those in the middle and workingclasses who had scrimped and saved forretirement. Private charities were over-whelmed, and public charity dried up as state and municipal tax collectionsplummeted. Only a few Civil War vet-erans and their widows received smallpensions; otherwise, private pensionswere rare. The ½rst Social Security check was not paid until the 1860 co-hort reached age 80, and few were eligi-ble for bene½ts. For the one-third of the1860 cohort who survived to their sixty-ninth birthdays, the ½nal years were gen-erally grim.

America’s 1890 cohort also livedthrough boom and bust. World War Iended a recession. With peace cameanother recession; unemploymentreached 12 percent. The 1920s broughtboom, except on the farm. The year 1929 ushered in twelve years that blight-ed what should have been this cohort’sprime earning years. Too old to ½ght in World War II, the men of the 1890cohort worked to support their sons at the front. Women left home for thepaid labor force, freed from traditionaljobs as secretaries, teachers, social work-ers, and nurses, to become machinistsand assembly-line operatives.

Like its forebears, the 1890 cohort suffered high rates of infant mortality.Although this cohort bene½ted fromsteady, if undramatic, improvements in health and education, more than one-third of 20-year-old women andtwo-½fths of 20-year-old men did not



live to see their sixty-½fth birthdays.Eighty percent of unmarried elderlywomen and half of unmarried elderlymen had been widowed. Four-½fths of this cohort ½nished primary school,one-fourth graduated from high school,but only one in twenty earned a collegedegree.

When this cohort reached age 65 in themid-1950s, fewer than half had healthinsurance. Coverage was often uncertainbecause insurers could raise premiumssharply or refuse to renew coverage ofthose whose health had begun to dete-riorate. Because health expenses of theelderly, even when adjusted for inflation,were less than one-tenth of what theyare today, medical outlays were a threatonly for the minority who became seri-ously ill. But in one of the most strikingsocial changes of the late twentieth cen-tury, a spell in a nursing home becamecommon. By the late 1970s, roughly aquarter of the 1890 cohort survivorswere residing in nursing homes.

Congress passed the Social SecurityAct of 1935, subsequently increasingbene½ts and extending coverage in 1939and again in 1950. Because of these liber-alizations, members of the 1890 cohortreceived bene½ts far greater than theearmarked payroll taxes they and theiremployers had paid. Still, bene½ts weremodest–only about 32 percent of tax-able earnings of full-time covered work-ers. And since roughly half of U.S. jobswere not covered until the 1950 legisla-tion broadened coverage, many mem-bers of the 1890 cohort did not receivebene½ts at all. Furthermore, private pen-sions covered only about a quarter ofmembers of the 1890 cohort. Even work-ers who were covered typically receivedmeager bene½ts because most had notworked long enough under these plansto have earned meaningful bene½ts.With insuf½cient income to retire, two-

thirds of surviving men from the 1890cohort were still working at age 65, near-ly half at age 70, and 30 percent at age 75.More than one-third had incomes belowof½cial poverty thresholds.

The 2.6 million American childrenborn in 1930 enjoyed advantages un-available to previous generations. Near-ly all ½nished primary school. Seven inten graduated from high school. Part-ly because of the G.I. Bill for Korean War veterans, one man in ½ve and onewoman in nine graduated from college.Women no longer automatically with-drew from the labor force after mar-riage; those who did often reenteredwhen still young. Just over one-thirdworked outside the home when theywere age 30, but three-½fths did at age50, and two-½fths still worked for pay at age 60.

If the educational achievements ofthe 1930 cohort were striking, the eco-nomic advances were breathtaking.Between the end of World War II andthe mid-1970s, output per person morethan doubled. At the start of their work-ing lives, members of the 1930 cohortearned hourly wages three times higherthan members of the 1890 cohort hadearned in their ½rst jobs. By the time the1930 cohort turned age 65, their averageearnings had risen by another one-third.Post–World War II recessions, thoughnumerous, were shallow compared withthe economic paroxysms of earlier eras.Furthermore, unemployment compen-sation, also created by the Social Securi-ty Act of 1935, cushioned the shock forthose who did lose jobs–for up to sixmonths in normal times and even lon-ger during recessions.

Higher incomes, medical advances,and improved working conditions com-bined to boost life expectancy for the1930 cohort. Two-thirds of men and over



three-quarters of women born in 1930lived to celebrate their sixty-½fth birth-days. Four-½fths of 65-year-old men andthree-½fths of 65-year-old women stilllived with a spouse.

As they approached retirement age inthe mid-1990s, members of the 1930 co-hort had options and resources few oftheir parents had enjoyed. Most had as-sets that provided substantial ½nancialsecurity. Social Security bene½ts, aver-aging $8,500 a year for individuals and$12,000 for couples, were fully protectedagainst erosion by inflation. One-thirdof the 1930 cohort received private pen-sions, although the amounts were mod-est–a median of less than $7,000 a year.Further, more than four in ½ve mem-bers of the 1930 cohort owned their own homes at retirement. Most hadbene½ted from the postwar real-estateboom that tripled the real value of own-er-occupied housing between 1950 and1995. The 1930 cohort also had betterprotection against medical costs thanever before. Medicare, enacted in 1965,provided basic health insurance cover-age for the elderly and the disabled whileeight in ten also had supplementary cov-erage.

Increasingly workers retired years be-fore they died. One-third of men in the1930 cohort stopped working before age62, two-thirds before age 65. Average living standards approximated those ofyounger adults. Averages, however, con-cealed large disparities: only 4.3 percentof elderly couples were poor in 1996,compared to 18 percent of elderly singlemen, 20 percent of elderly single wom-en, and 36 percent of elderly single Afri-can American women. Whatever the fu-ture holds for the ½nal years of the 1930cohort, its circumstances represent arevolutionary improvement over theexperiences of their predecessors.

America’s 1960 cohort was better edu-cated than any of its forebears. Only onein eight dropped out of high school. Halfattended college and nearly one-fourthearned a bachelor’s degree. The fractionof the 1960 cohort with postbaccalaure-ate education matched the share of the1860 cohort who had completed highschool. But not all advanced at the samepace. African Americans were only two-thirds as likely as whites to earn a collegedegree, and barely half of Hispanicscompleted high school.

Even if the earnings of men with littleeducation grew more slowly than theirparents’ pay had, the 1960 cohort earnedmore on their ½rst jobs than their par-ents had three decades earlier. The jobs½lled by members of the 1960 cohortalso required less brawn and more brainthan had jobs in the past. Three-½fths of men and 90 percent of women in the1960 cohort worked in white-collar orservice-sector jobs. Still, roughly one-quarter of men and a small but growingfraction of women worked as craftsmen,mechanics, miners, machine operators,laborers, truck drivers, or in other phys-ically strenuous jobs that become in-creasing dif½cult to perform as one ages.Women were better educated, workedmore hours, stayed in the labor forcewith fewer interruptions, and earnedmuch more than women had previously.As a result, more will be entitled to theirown private pensions and to Social Secu-rity based on their earnings rather thantheir husbands’.

Members of the 1960 cohort have toldpollsters that they hope to retire earlierthan have past generations. Unfortu-nately, they have done little to prepareeconomically for that event. By 2000,only 31 percent of those born between1954 and 1964 had nonhousing assetsworth more than $100,000, and 49 per-cent had accumulated less than $50,000,



a sum that would support an annuity ofless than $4,000 a year. In their failure to save, the 1960 cohort differ little fromtheir forebears, who began to save, ifat all, only in their forties and ½fties.Members of the 1960 cohort may ½nd it even harder to save when they reachthose ages, though, because many mar-ried late and deferred childbearing. As a result, many will face tuition bills andother costs of childrearing until late intheir lives.

On the bright side, more members of the 1960 cohort will have more size-able pensions than previous genera-tions. The declining fraction of employ-ees with pensions tied to previous earn-ings, so-called de½ned-bene½t plans, will ½nd them more secure than in thepast because the Employee RetirementIncome Security Act of 1974 set vestingrules and the Pension Bene½t GuarantyCorporation guarantees all or much ofpromised pensions. On the other hand,the massive shift to pensions whosevalue depends on the market price ofstocks and other assets, so-called de-½ned-contribution plans, means that the pensions of the 1960 cohort will face the risk of losing value just whenthey are needed. If the pensions are notconverted into annuities, these risks willpersist even after bene½ts are being paid.More than previous cohorts, membersof the 1960 cohort will also confront thepossibility that they will outlive their as-sets. One-½fth of men who reach age 65are projected to be alive at age 90, andhalf of women alive at age 65 are expect-ed to live past their eighty-seventh birth-days.

If members of the 1960 cohort retirewhen they say they will, those who reachretirement age will spend an average ofroughly one-third of their adult lives inretirement. But retirement patterns maychange as rising budgetary costs force

cutbacks in publicly ½nanced pensionand health bene½ts. Out-of-pocket medical expenditures may discourageolder people from leaving primary jobs as soon as they now do or fromwithdrawing from the labor force com-pletely.

Undeterred by the demonstrated in-capacity of even the brightest people toanticipate future conditions or events,many claim to see clearly into the dis-tant future. David Cutler, a Harvard pro-fessor and dean, once spoke disparaging-ly of “spreadsheet policy analysis,” theextraordinary disposition of some ana-lysts to take seriously the mindless ex-trapolation of unreliable assumptionsdecades or even centuries into the fu-ture. What should be clear to all who tryto anticipate the implications of popula-tion aging for today’s and tomorrow’snewborns is that only a few things areclear.

One, the proportion of the populationthat is elderly will increase. This trend isalmost certain because the large cohortsof baby boomers who will start reachingage 65 in 2008 are already alive. Almostas certain is that tomorrow’s elderly, liketoday’s, will be mostly women. Of thoseover age 65, 58 percent are female; ofthose over age 85, 69 percent are female.Female life expectancy exceeds male lifeexpectancy by about ½ve years. As wom-en are also typically younger than theirhusbands, women are more likely to out-live their husbands and can anticipateabout ten years of widowhood.7 It is al-so likely that life expectancy will con-



7 The Social Security Administration estimatesthat among couples in which the husband is 65and the wife is 63, 54 percent of women and 45 percent of men will outlive their spouses bya year or more (the remainder will die in thesame year). Women will outlive their husbandsby an average of 10.84 years; widowers will out-

tinue to increase, though by how muchremains highly uncertain.8 However, adrop in longevity, caused by widespreadobesity or a global pandemic that sci-ence is unable to control, is not out ofthe question.

In any event, the physical and men-tal condition of the elderly during theseadded years counts more than the merenumber of years added to the human life span.9 A nation swarming with dod-dering seniors incapable of working oreven of caring for themselves would facenasty challenges. On the other hand, anation replete with mentally and physi-cally active elders who might even delayretirement a few years would enjoy anextraordinary economic and social op-portunity. The speed and character ofadvances in medical knowledge give rea-son for optimism, if not for con½dence,that increased longevity will lengthenlife, not prolong dying. Understandingand controlling the processes that un-derlie Alzheimer’s disease and otherforms of senile dementia and arthritisare within the reach of medical science.

Subject to these uncertainties, the na-tion of 2050 is quite likely to be richerand better educated than its forebears,even if the rate at which longevity in-creases slows. Growth of per capita in-come will continue as the fruits of in-formation technology, such as data processing that abets advances in mo-lecular biology, continue to spread.10According to estimates by Kevin Mur-phy and Robert Topel, the welfare gainfrom increased longevity between 1970and 2000 was worth about as much as all economic growth over that period.11Factors other than advances in healthcare contributed to this increase, ofcourse. But improvements in the treat-ment of heart attacks and reductions in the number of low– birth weight in-fants yielded bene½ts worth about sixand ½ve times the added cost of medi-cal care respectively.12 And eliminatinghalf the deaths from heart disease orcancer would produce bene½ts greaterthan annual gdp to current and futureAmericans. Moreover, these estimatesmake no speci½c allowance for enhance-ments in the quality of life that wouldresult from better medical care.



10 J. Bradford DeLong, Claudia Goldin, andLawrence F. Katz, “Sustaining U.S. EconomicGrowth,” in Agenda for the Nation, ed. Henry J. Aaron, James Lindsay, and Pietro Nivola(Washington, D.C.: Brookings InstitutionPress, 2003), 17–60.

11 Kevin M. Murphy and Robert H. Topel place the gain from increased longevity at $3.2trillion a year. gdp rose from just over $1 tril-lion in 1970 to just over $9 trillion in 2000. SeeKevin M. Murphy and Robert H. Topel, “TheValue of Health and Longevity,” The NationalBureau of Economic Research, Working Paper11405, June 2005.

12 David M. Cutler and Mark C. McClellan, “Is Technological Change in Medicine WorthIt?” Health Affairs 20 (5) (September/October2001): 11–29.

live their wives by an average of 9.75 years. Per-sonal communication from Stephen Goss, chiefactuary of the Social Security Administration.

8 James Vaupel thinks that today’s newbornswill typically live into the next century. Otherdemographers simply extrapolate trends of themore or less recent past and predict that life ex-pectancy will continue to increase one or twoyears with each passing decade. Jay Olshanskyand various colleagues worry that obesity, pan-demics, or other events will reverse the increasein life expectancy.

9 Alexander M. Capron, “Ethical Aspects ofMajor Increases in Life Span and Life Expec-tancy,” and Margaret Battin, “Comments,” inHenry J. Aaron and William B. Schwartz, Cop-ing with Methuselah: The Impact of MolecularBiology on Medicine and Society (Washington,D.C.: Brookings Institution Press, 2004),198–234, 235–246.

It is possible that future advances maynot bring bene½ts as large as those ofpast innovations. The twenty-½rst cen-tury has a tough act to follow: the twen-tieth century saw massive reductions ininfant and childhood mortality, the in-troduction of arti½cial joints and ctand mri scans, and the virtual elimina-tion of broad classes of infectious dis-eases. But this century has opened aus-piciously with the sequencing of thehuman genome, an event that may re-veal the fundamental processes of par-ticular illnesses and of biological agingand senescence and heralds the possi-bility of individualized medicine, wheretreatments are tailored to the speci½c bi-ological characteristics of each person.Even if the twenty-½rst century does not live up to the more overheated ex-pectations of some observers, there isgood reason to hope that Alzheimer’sdisease, diabetes, and some forms ofcancer will become curable or even pre-ventable. These improvements will becostly, however. In fact, they are likely to be so expensive that they will forceextremely dif½cult and divisive politi-cal choices and economic tradeoffs. Buttechnical advance will be a cruel tease iffew can afford it.

Total spending on the products madepossible by scienti½c revolutions typi-cally increases, even as the prices ofthese products fall. The automobile, theairplane, television, and the computerreduced the price of moving a person or a ton of merchandise a mile, of hearingan opera or seeing a drama, and of car-rying out an arithmetic computation. Atthe same time, they raised total spendingon these activities because they raisedthe standards of quality, thus increasingthe quantities that people demanded. Noone bewailed the growth in the share ofincome devoted to transportation, enter-

tainment, or computation, however. In-stead, as other, less satisfying forms ofconsumption gave way to the new tech-nologies, people celebrated the improve-ment in living standards.

So also demand for medical treat-ments has dramatically increased asmedical advances have improved thechances for bene½cial outcomes whilereducing the price of achieving theseoutcomes. Largely because of such ad-vances, total U.S. spending on healthcare multiplied more than ninefold and tripled as a share of gdp between1960 and 2003. There is every reason toexpect future medical advances to add to age-adjusted, per capita spending onhealth care. Population aging will ampli-fy this growth, but advances in medicaltechnology are likely to remain the prin-cipal force driving up health-care spend-ing.13

If health-care spending were to con-tinue growing at the same rate as in the past half century, about 2.5 percent-age points a year faster than the growthof per capita income, the fraction ofincome devoted to health care would reach 33.6 percent in 2030 and 36.1 per-cent in 2040. Increases in health-carespending would claim half of incomegrowth by 2022 and all of it by 2051. IfMedicare and Medicaid spending wereto rise at the same rate, outlays on thesetwo programs alone would rise from 4.2percent of gdp in 2005 to 11.5 percent by 2030, and 16.1 percent by 2040.14 For



13 Per capita health-care spending rises untilpatients are in their eighties and then it actual-ly falls.

14 Henry J. Aaron and Jack Meyer, “Health,” inRestoring Fiscal Sanity: The Long-term Challenge,ed. Alice Rivlin and Isabel Sawhill (Washing-ton, D.C.: Brookings Institution Press, 2005).These projections are taken from the Congres-sional Budget Of½ce.

purposes of comparison, all income andpayroll taxes combined will comprise 16percent of gdp in 2006.

These projections suggest that taxes,premiums, and cost sharing will have toincrease and that coverage will have tobe restricted. A more dif½cult problemarises from the fact that most health care is consumed during episodes of ill-ness when total spending is so high thatany adequate insurance plan will coverall, or nearly all, costs at the margin. Inthis situation, patients have economicincentives to seek, and conventionallyreimbursed providers have every incen-tive to assure that patients receive, allcare however high the cost or low thebene½t.

Health-care rationing curbs such high-cost, low-bene½t care for well-insured patients. Most people and allpoliticians recoil now at the prospect of health-care rationing. This reaction is misplaced because such rationingwould improve welfare by redirectingresources from uses that produce ben-e½ts smaller than cost and make themavailable for services that produce ben-e½ts greater than cost. Whether the na-tion can ration health care accuratelyand fairly, though, is far from certain,but trends in health care indicate that a national debate about health-care ra-tioning is inescapable.15

Even with higher cost sharing andwell-designed rationing, Americans–and citizens of all other advanced na-tions–are going to end up paying farmore than they now do for health care.Population aging will intensify thistrend.

Even if maturity brings certain com-pensations and opportunities,16 no onewelcomes the loss of physical and men-tal capacities associated with aging. Butthe problems that aging individuals faceis not the cause of ‘aging angst.’ Rath-er, it stems from a sense that a large in-crease in the fraction of people who are‘old’ will make life much less attractivefor the young. The fear is that the el-derly will be economically inactive andotherwise unproductive, that they willnot have saved enough during their eco-nomically active years to provide forthemselves during their inactive years,and thus, that they will impose crushingtax burdens on the declining fraction ofthe population who are economicallyactive.

It is certainly possible for nations tobring calamity on themselves throughmismanaged policies, as the histories of Argentina throughout the twentiethcentury, most of Africa after the end ofcolonial rule, and the Russian empireunder communism clearly attest. But wecan manage the problems of populationaging easily. To do so, American policy-makers need to keep a few basic facts in mind. First, apart from borrowing or lending from foreigners, all nationalconsumption comes from currently pro-duced goods and services. How that con-sumption is divided between the eco-nomically active and inactive dependson the relative size of these two groupsand their relative living standards. Sec-ond, consumption by the economicallyinactive can be ½nanced either by theirown past savings or by current taxes onthe economically active. Third, past sav-ings are responsible for today’s capital



16 George E. Vaillant, Aging Well: SurprisingGuideposts to a Happier Life from the LandmarkHarvard Study of Adult Development (Boston:Little, Brown, 2002).

15 Henry J. Aaron, William B. Schwartz, andMelissa Cox, Can We Say No: The Challenge ofRationing Health Care (Washington, D.C.:Brookings Institution Press, 2005).

stock, which influences today’s produc-tive capacity. Finally, past savings alsocan be used to support today’s elderly.

The lesson of these simple economicrelations is straightforward. Americanscan prepare now to meet the macroeco-nomic ‘challenge’ of aging by insistingon public policies to promote high na-tional saving. That will add to tomor-row’s productive capacity. High savingwould also reduce borrowing fromabroad, which generates debts to for-eigners that tomorrow’s active work-ers will have to either repay or pay debtservice.

Yet recent economic policy has movedresolutely in the direction of encourag-ing consumption with permanent taxcuts. Recent discussions of pension re-form have also lacked explicit proposalsto encourage future generations of work-ers to delay retirement, which would re-duce pension claims. By extending drugcoverage to the elderly and disabled,Congress has further committed thenation to providing a needed bene½t but failed to pay for it, thereby increas-ing borrowing and deepening the fu-ture ½scal challenges of population ag-ing. Measured over the next seventy-½veyears, the Medicare Modernization Actwill also add to federal borrowing anamount nearly twice the projected short-fall in Social Security. Thus, current poli-cy has aggravated, rather than ameliorat-ed, the ½scal problems of population ag-ing.

The ½rst step in dealing with the ‘ag-ing problem’ is to avoid public policiesthat enlarge it.

The second step is to recognize thatthe U.S. ‘aging problem’ is among thesmallest in the developed world.

The third step is to recognize thatalthough population aging will pre-sent some ½scal challenges, it is the by-

product of a monumentally bene½cialachievement–increased longevity–andan inevitability–declining birth rates.

Longer life spans will doubtless createsome problems. But as the old sayinggoes: Consider the alternative.




Last scene of all, that ends this strange eventful history,

Is second childishness, and mere oblivion . . .

–Shakespeare, As You Like It

Before the last century, only a smallportion of the human population sur-vived into the eighth decade of life.Those few individuals who successful-ly avoided the myriad causes of adultmortality–principally, infectious dis-eases, trauma, and cardiovascular fail-ure–were expected to face a steady at-trition of their most human qualities:

memory, reasoning, judgment, abstrac-tion, and language. In the popular mind,and even among scientists and philoso-phers, the idea that great age inevitablybrought about an inability to think clear-ly was widely accepted. But intensive re-search into the pathology and biochem-istry of the aging brain during the lastfew decades has revealed that speci½cdiseases cause major impairment of cog-nition late in life and that the process of aging per se results only in relativelysubtle changes in certain mental func-tions.

This reinterpretation of the nature ofthe aging mind has profound implica-tions on both the personal and societallevels. In contrast to the assumption in-herent in Jacques’ soliloquy, the passingof time does not by itself destroy ourability to think cogently. Rather, certaindiseases that devastate those areas of thebrain serving memory and cognition be-come increasingly prevalent after age 70or so. For example, the two major causesof late-life dementia in most developednations, Alzheimer’s disease and multi-ple small strokes (multi-infarct demen-tia), afflict just a few individuals in theirforties or ½fties, but the numbers risevery substantially in the mid-sixties andbeyond.

In this sense, aging, the passage oftime, does contribute to the develop-

Dennis J. Selkoe

The aging mind: deciphering Alzheimer’s disease & its antecedents

Dennis J. Selkoe is Vincent and Stella Coates Pro-fessor of Neurologic Diseases at Harvard Medi-cal School and the Brigham and Women’s Hos-pital. He cofounded and serves as cochair of theHarvard Center for Neurodegeneration and Re-pair. Selkoe was the principal founding scientist of Athena Neurosciences, now Elan Pharmaceu-ticals. Widely published in the ½eld of Alzheimer’sdisease research, Selkoe has received numeroushonors, including the Dr. A. H. Heineken Prizefor Medicine from the Royal Netherlands Acade-my of Arts and Sciences and the Potamkin Prizefrom the American Academy of Neurology.


ment of dementing diseases in at leasttwo broad ways. First, over time, thebrain accrues molecular and cellulardefects in neurons and glia, which re-duce its physiological reserve, just asoccurs in muscle cells with age. Thisprocess makes the brain more suscep-tible to loss of function if and when aneurological disease is imposed. Second,some of the speci½c diseases that causedementia require great time to produceenough brain abnormalities, or lesions,to compromise function. For instance, in Alzheimer’s disease and certain oth-er dementias, a lot of time is needed toreach a critical tissue concentration ofparticular proteins that allows for theirpolymerization into potentially toxicforms. In short, the process of brain ag-ing can contribute to the development of a clinically noticeable dementing ill-ness, but aging by itself appears to be in-suf½cient to cause the illness.

Life expectancy at birth in the UnitedStates and in many other developed na-tions has risen from roughly ½fty yearsin 1900 to more than seventy-½ve yearsin 2000, an unprecedented 50 percentincrease in just one century. This sud-den jump in average longevity is theresult of major improvements in publichealth, intensive biomedical research,and subsequent pharmacological, surg-ical, and lifestyle interventions. It is byno means assured that life expectancywill continue to rise in the coming cen-tury, with the threat of highly resistantinfectious diseases and an emerging ep-idemic of obesity and associated meta-bolic disease.1 Nevertheless, the sheernumber of humans now surviving be-

yond eighty years and the accompany-ing social and economic stresses demandthat the scienti½c community focus farmore attention on the determinants ofsuccessful aging and the prevention ofage-linked disease–particularly in thebrain, which helps regulate non-neuralorgan function.

Based on personal observation, manypeople have come to realize that the ag-ing process does not usually wreak hav-oc on the mind. But as recently as thirtyyears ago, gerontologists and neurosci-entists were not at all sure of this conclu-sion and continued to catalog a complexarray of relatively minor de½cits in thenumbers and biochemical properties of brain cells in aged mammals, includ-ing humans. Understandably, scientistsfocused mostly upon the health of neu-rons, the excitable cells in the brain thatconvey signals through electrochemicalimpulses–for example, a response tolight impinging upon the photoreceptorcells of the retina or to sound waves vi-brating the hair cells of the inner ear.Because the long cytoplasmic exten-sions of neurons, the axons and den-drites, pass information from one placeto another in the brain, age-related de-fects in the innumerable molecules thatallow them to do so could lead to cogni-tive failure. Indeed, scientists have docu-mented a host of quantitative and quali-tative changes in neuronal receptors, en-zymes (specialized proteins that catalyzechemical reactions), structural proteins,and lipids in the brains of aged rodents,lower primates, and humans.

But when one counts the actual num-bers of surviving neurons in aged versusmiddle-aged or young brains, most brainregions show very little or no signi½cantneuronal attrition. This recent realiza-tion flies in the face of the long-held as-sumption that neurons steadily die outduring the life span, a conclusion based

Deciphering Alzheimer’s disease & itsantecedents

1 S. J. Olshansky et al., “A Potential Decline inLife Expectancy in the United States in the 21stCentury,” New England Journal of Medicine 352(2005): 1138–1145.



Dennis J.Selkoeonaging

on what we now recognize as technicallyflawed cell-counting methods. For ex-ample, the number of pyramidal neu-rons in certain areas of the hippocam-pus, a seahorse-shaped brain region crit-ical for memory, does not decline appre-ciably in older humans.

On the other hand, the number ofneurons in the substantia nigra–a smallcluster of neurons in the brain stem thatsecrete the neurotransmitter dopamine–does decline steadily with age, perhapsbecause these cells produce the pigmentneuromelanin as a by-product of theirdopamine metabolism, a process thatresults in the excessive oxidation of pro-teins and lipids. The age-related dys-function and loss of substantia nigra neu-rons likely contributes to the decreasedspeed and fluidity of movement andsomewhat stooped, shuffling gait thatvery old people often display. This ½nd-ing provides an example of the relation-ship of the aging process in the brain todiseases of the elderly. Age-associatednigral cell loss, which may normallyamount to 30 to 50 percent or so of theseneurons, is not suf½cient to induce theclinical syndrome of Parkinson’s dis-ease. However, this level of attrition mayreduce the physiological reserve enoughso that a superimposed insult, e.g., thepresence of an inherited mutation in aspeci½c gene or prolonged exposure toan environmental toxin, may elevate thedegree of nigral cell loss to some 70 to 80 percent, enough to produce clinicallyapparent symptoms of Parkinson’s dis-ease. But it must be added that the lossof neurons during normal aging in thesubstantia nigra is more severe and pre-dictable than one observes in many oth-er regions of the brain such as the cere-bral cortex.

Even when the absolute number ofneuronal cell bodies does not decline

substantially, the brains of older mam-mals reveal a remarkable array of cellu-lar and molecular alterations. There aredefects in nuclear and mitochondrialdna; in many different proteins, partic-ularly enzymes; and in the lipids of themembranes enveloping cells and inter-nal organelles. What bearing do thesediverse molecular changes have on themind?

For most of us, the answer is very lit-tle. In aged people without Alzheimer’sdisease and other mind-threatening ill-nesses, the clinical effects of biochemi-cal and anatomical alterations seem tobe modest. In many studies reportingage-related neurochemical de½cits–such as a reduction in a particular en-zyme or in certain proteins or rna mol-ecules–the levels or functional activitiesin elderly adults have ranged from 5 to 30 percent below those in young adults.And though a 30 percent loss mightseem quite high, such gradual declinesover several decades often have littlemeasurable effect on thinking. Indeed,positron emission tomographic (pet)scans and functional magnetic reso-nance imaging (fmri) scans show thatthe brains of healthy people in theireighties are almost as active metaboli-cally as those of people in their forties.In some brain regions such as parts ofthe frontal cortex, healthy aged humansmay even exhibit more metabolic activ-ity, though it is unclear whether thisseemingly paradoxical rise in activityrepresents the brain’s attempt at com-pensation for some neuronal loss or justa nonspeci½c and potentially adverse re-cruitment of remaining local neurons.2Overall, the aged brain tolerates relative-

2 R. L. Buckner, “Memory and ExecutiveFunction in Aging and ad: Multiple Factorsthat Cause Decline and Reserve Factors thatCompensate,” Neuron 44 (2004): 195–208.

ly small de½cits in neuronal structureand function rather well, although cer-tain mental functions required for high-ly specialized activities–such as the rap-id visual-motor tasks required to pilot a 747 or perform complex surgery–maybecome compromised in older humans.

Epidemiological and neuropsycholog-ical studies generally paint a similar pic-ture to that emerging from neurobiologi-cal research. Estimates of the prevalenceof senile dementia–the progressive lossof cognitive function after roughly age65–vary widely, but most data suggestthat a large majority of individuals intheir seventies and eighties are free ofsigni½cant cognitive loss that interfereswith daily function. And analyses ofhealthy elderly adults reveal only sub-tle declines in performance on tests of memory, perception, and language.One decrement on which numerousstudies agree, however, is a reduction inthe speed of some aspects of cognitiveprocessing. Hence, septuagenarians areoften unable to quickly retrieve certaindetails of a particular past event–say,the precise date or place–although theyare often able to recall the informationminutes or hours later. Given enoughtime and an environment that keepsanxiety at bay, many healthy elders scorealmost as well as young or middle-agedadults on tests of mental performance. A measure of guarded optimism emergesfrom investigations of ‘normal brain ag-ing’: one may not learn or remember asrapidly later in life, but one may learnand remember nearly as well.

The range of brain diseases that expressthemselves as a progressive loss of intel-lectual function is remarkably broad.Vascular, metabolic, infectious, neoplas-tic, traumatic, and degenerative disor-ders can all present with symptoms ofdementia.

At different times over the course ofthe last century, various disorders haveassumed greater or lesser relative impor-tance in contributing to late-life demen-tia. In the early 1900s, for example, neu-rosyphilis was considered a commoncause of dementia; Alzheimer’s diseasehad not yet been recognized as a speci-½c brain disorder. More recently, theproportion of dementia cases attributa-ble to one or more strokes has declinedbecause of the successful control of hy-pertension and hyperlipidemia and thegradual reduction in some types of car-diovascular disease. When Alzheimer’sdisease comes under reasonable medi-cal control, other disorders will assumegreater relative importance in the differ-ential diagnosis of late-life dementia.

But in developed countries today, Alz-heimer’s disease is still by far the mostcommon basis for senile dementia,accounting for some one-half to two-thirds of all cases. For several decadesafter Alois Alzheimer reported his indexcase, a 53-year-old woman from Frank-furt, the disorder was classi½ed as a rare‘presenile’ dementia, that is, a dementiahaving its onset prior to roughly age 65.But in the mid-1960s, three British scien-tists–Garry Blessed, Bernard Tomlin-son, and Martin Roth–conducted land-mark clinical-pathological correlativestudies that made clear what some ear-lier investigators had suspected: com-mon senile dementia is usually associat-ed with the classical ½ndings in the brainthat Alzheimer had described. The term‘senile dementia of the Alzheimer type’was subsequently coined, but nowadays,‘Alzheimer’s disease’ designates thissyndrome, regardless of the age of onset.For research purposes, one still refers to‘early-onset ad’ and ‘late-onset ad,’ di-vided arbitrarily at age 65, but little evi-dence exists that these are fundamental-ly distinct biological processes or that





we could not ultimately treat them asone entity.

In the United States, multi-infarct de-mentia has long been considered thesecond most common basis for late-lifedementia, even though Parkinson’s dis-ease-associated dementia plus a relateddisorder, Lewy body dementia (namedafter the characteristic neuronal lesionthat de½nes Parkinson’s disease), arenow equally if not more prevalent. Care-ful microscopic analyses of autopsiedParkinson’s disease brains often revealthe features of ad or else ad plus Lewybody dementia, confounding precisediagnostic classi½cation. Nevertheless,‘pure’ Alzheimer’s disease is still themost common neuropathological ba-sis for late-life dementia in the UnitedStates and most developed countries. A number of less common causes of de-mentia, including frontotemporal de-mentia and Creutzfeld-Jakob disease,share certain pathological or biochemi-cal features with ad, but they are etio-logically distinct.

Virtually everyone beyond late middleage has worried that an occasional mem-ory lapse–a name forgotten or an objectmisplaced–could represent the earliestsign of ad. But such momentary losses,with recovery of the detail within min-utes and a complete awareness of thelapse, are usually not progressive. Incontrast, the repeated inability to re-member recent, minor episodes of dai-ly life–a call from a friend, a trip to thedepartment store, the paying of a bill, a brief news story–can represent theearliest harbinger of ad. In a conditionnow referred to as ‘mild cognitive im-pairment (mci)-amnestic type,’ theindividual shows a subtle, intermittentdecline in episodic memory but is oth-erwise intact cognitively and performsvery well in everyday life. Evidence fromstructural and functional magnetic reso-

nance imaging of mci-amnestic brainssuggests that the neuronal dysfunction is restricted to the hippocampus and a small number of other brain struc-tures connected to it. Studies of the fateof mci-amnestic subjects over time sug-gest that roughly 12 to 15 percent of them‘convert’ to clinically diagnosable, mildad each year, meaning that these indi-viduals begin to exhibit signs of a moregeneral disturbance of recent memory as well as disorientation to time andplace, decreased attention span, confu-sion in executing complex tasks, andsometimes, dif½culty in ½nding words.This slow progression of cognitivesymptoms occurs in an individual whoappears fully alert and demonstrates noabnormalities of the motor system, e.g.,decreased mobility, stiffness, and slowedgait, until later in the disease.

What causes this initially subtle butultimately devastating loss of higher cortical function? The answer has be-gun to emerge from three decades ofintensive neuropathological, biochem-ical, and genetic research. While there is still earnest debate about the detailedsequence of events, the majority of sci-entists researching ad now believe thatthe misfolding, aggregation, and accu-mulation of a small protein of forty-twoamino acids, the amyloid ß-protein (aß),initiates a complex cascade of molecularand cellular changes that compromiseneuronal function in brain regions serv-ing memory and cognition.

According to this scenario, widelyreferred to as the ‘amyloid (or aß) cas-cade hypothesis,’ a chronic imbalancebetween the production and the clear-ance of this otherwise normal proteinarises in the brain long before the ½rstsymptoms of dementia. This accumu-lation leads to the self-association ofaß into ‘oligomers’ (doublets, triplets,

quadruplets, etc.), which in turn canassemble into ½lamentous polymers(‘amyloid ½brils’) that clump together to form the cores, or spherical centers, of tiny plaques. These amyloid depositsare gradually surrounded by degenerat-ing axons and dendrites (collectivelycalled neurites) and activated brain in-flammatory cells (microglia and astro-cytes), completing the formation of so-called neuritic plaques.

During this slowly evolving process,some of the neurites within and adja-cent to the emerging plaque develop rig-id intracellular ½laments, or ‘paired he-lical ½laments,’ that are composed ofa neuronal protein called tau. Tau ½la-ments also accumulate in large bundlesthat comprise the neuro½brillary tanglesfound inside many neuronal cell bodiesin the hippocampus and cerebral cortex,as well as in certain subcortical neuronsthat send their axons to these areas. Inshort, the accumulation and self-assem-bly of the aß protein is believed to initi-ate a series of ½rst functional (biochem-ical) and then structural (anatomical)changes in selected neurons, to the ul-timate detriment of the thinking pro-cess.

Perhaps the most compelling evi-dence for this aß hypothesis has comefrom identifying and characterizinggenetic mutations that cause rare inher-ited forms of ad. It is a truism of mod-ern biomedicine that searching patients’genomes for faulty genes opens up thestudy of diseases of previously unknowncause and mechanism. For example, un-til the cloning of the Huntington gene in 1993, no one had any real clue as towhat might be killing off certain brainneurons in patients with Huntington’sdisease. In this and many other heritablediseases, the unbiased search of the hu-man genome for the genes responsiblefor the disease allowed scientists to sub-

sequently formulate biochemical hy-potheses about what actually kills cells.But in the case of Alzheimer’s disease,the opposite sequence occurred: prog-ress in the 1980s in understanding thebiochemistry of the disease identi½edthe proteins that comprise the plaquesand tangles, providing geneticists withkey clues to the location of the dna mu-tations that might cause Alzheimer’s dis-ease.

In 1991, researchers discovered the ½rstmutation responsible for ad on chromo-some 21, speci½cally in the gene that en-codes the amyloid precursor protein(app), the parent protein of aß. In addi-tion to the fact that app molecules giverise to the aß fragments that form theneuritic plaques, a crucial clue that theapp gene might be the site of an ad-causing defect came from a disorder at the opposite end of the life span:Down syndrome. Humans with Downsyndrome, or trisomy 21, the most com-mon form of chromosomal duplicationcompatible with life, invariably developthe plaques and tangles of ad in theirthirties and forties. This is because theyharbor three copies of the app gene inall of their cells, rather than the usualtwo copies. The extra copy of the appgene results in a roughly 50 percent in-crease in the cellular levels of the appprotein throughout life and the conse-quent start of aß deposition in the Downsyndrome brain as early as age 10.

Another powerful clue pointing to the app gene had come from studying a family in the Netherlands with a his-tory of multiple brain hemorrhagescaused by the severe build-up of the aß protein in cerebral blood vessels. In1990, scientists discovered that a muta-tion in the app gene that changes a sin-gle amino acid within the aß region ofapp was responsible for this rare disor-der, demonstrating for the ½rst time that





mutations in app could cause aß accu-mulation.

With all of this knowledge in hand,geneticists scrutinized the app region of chromosome 21 in a few families witha hereditary form of ad that led to theonset of dementia in the ½fties. In onesuch family, they discovered a ‘missense’mutation in app that changed one ami-no acid near the end of the sequenceencoding the aß region to another. Thestudy of other families with early onsetof ad revealed additional app missensemutations, most of which occurred inamino acids either at the beginning or at the end of the forty-two-residue aßregion. Tellingly, geneticists did not ½ndany ad-causing mutations away fromthe aß region of this large (770–aminoacid long) precursor protein, indicatingthat the mutant amino acids might leadto increased cutting of app at the begin-ning or end, resulting in the heightenedproduction of the aß fragment.

As these genetic ½ndings were emerg-ing, a major biochemical discovery wasmade: all cells normally produce the aßpeptide throughout life. Thus, aß is theproduct of healthy app metabolism inall of us, implying that unknown factors–genetic, environmental, or both–canincrease its production or decrease itsdegradation in those individuals whodevelop ad, all of whom have too muchaß in their brains.

Putting together these two key obser-vations–that healthy cells continuallymake aß and that rare mutations withinits precursor, app, can cause ad–led togroundbreaking experiments. Insertinga gene that bore an ad-causing app mu-tation into cultured cells resulted in sig-ni½cantly greater aß production. Scien-tists could now study many details ofthe production and metabolic fate of aßin simple cell models. They could alsouse such cells to screen large libraries of

drug-like molecules and pinpoint com-pounds that lower aß production with-out damaging the cells. And through thewonders of genetic engineering, scien-tists could also create ‘transgenic’ micethat express a human app gene bearingan ad-causing mutation. After consider-able trial and error, the latter approachgenerated several highly useful mouselines that mimic several, but not all, fea-tures of ad in their brains, including the abnormalities of neurites and gliaaround the amyloid plaques. As they age, these mice develop de½cits in cog-nition such as dif½culty rememberinghow to negotiate mazes ef½ciently. Tak-en together, these and many other ex-periments have produced a wealth ofevidence that ad can arise at least inpart from an imbalance in the econo-my of the aß protein in brain regionsimportant for memory and cognition.The practical outcome has been to en-courage scientists to ½nd ways to loweraß levels in humans.

Still, there are many unanswered questions about the aß hypothesis.What causes the imbalance in aß levelsin the brains of the large majority of adpatients who do not have known genet-ic mutations? For example, can environ-mental factors influence the brain’s aßlevels? Does the aß peptide begin to ag-gregate inside the neuron before the aßoligomers are exported into the extracel-lular space and then bind back to thecell? Which type of brain cell–neurons,microglia, or astrocytes–is the ½rst torespond adversely to the excess of aß inthe local microenvironment? Preciselywhy do neuronal extensions, i.e., axonsand dendrites, respond with an aggrega-tion of their tau protein? Are the result-ant tau aggregates the prime culprits incompromising neuronal function andultimately killing the neurons? And per-haps most perplexing, how does the en-

tire process select for neurons servingmemory and cognitive function?

Answering all of these questions indetail should not be necessary in orderto treat or even prevent Alzheimer’s disease. Because human genetic data and the modeling of the effects of thefaulty genes in engineered mice havecontinued to support the aß hypothe-sis, scientists in both academia and thebiopharmaceutical industry have spentthe last decade devising strategies to in-terrupt the aß cascade at an early point in its development.3 Without know-ing precisely how aß compromises thefunctions of selected neurons, they havesearched for compounds that can de-crease brain aß levels, initially in mousemodels.

Three broad approaches have beenconceptualized. First, one could partial-ly inhibit one of the two specialized en-zymes, ß-secretase and γ-secretase, thatcut app to release the aß region. Second,one could allow these reactions, whichoccur normally in all of us, to proceedunimpeded but instead prevent a singleaß protein, a monomer, from bindingwith another to form oligomers, thesmall aggregates that appear to initiatethe amyloid build-up and the associatedshort circuiting of neurons. Third, onecould attempt to ‘clear’ the brain of var-ious forms of aß, including monomers,oligomers, and larger amyloid deposits.

The ½rst approach–inhibiting the protein-cutting enzymes that generateaß–is somewhat analogous to the use of statin drugs to decrease cholesterol

production. Several groups have iden-ti½ed inhibitors of ß-secretase, the en-zyme that cuts app ½rst. But these in-hibitors require modi½cation to makethem more potent yet still able to pene-trate the blood brain barrier and achieveeffective levels in brain tissue. At thiswriting, there are no such ß-secretaseinhibitors ready for human testing. Sci-entists have also discovered many smallmolecules able to inhibit γ-secretase, theenzyme that makes the second and ½nalcut of app. Unfortunately, most of thesemolecules also interfere with the cuttingby γ-secretase of a protein called ‘Notch’that is crucial for the normal function-ing of most cells. However, the serendip-itous discovery that certain anti-inflam-matory drugs like ibuprofen can gently‘tweak’ γ-secretase to lower the produc-tion of aß42, a particularly noxious formof aß, without decreasing Notch cleav-age has helped researchers continue topursue this approach. And since the anti-inflammatory properties of such drugsare not responsible for this selectivity,scientists have identi½ed and are nowtesting in humans derivatives that solelytweak γ-secretase. Early trial results sug-gest that these specialized ‘γ-secretasemodulators’ may indeed slow cognitivedecline, at least in some ad patients.

The second approach, preventing theself-assembly of aß into oligomers and½brils, makes good theoretical sense buthas received less attention. While somecompounds have performed well in test-tube experiments, very small assembliesof aß (dimers and trimers) can alreadyinterfere with synaptic function andbehavior, raising concern that a partialinhibition of aß aggregation might sta-bilize such small species and actuallyworsen the disorder.

The third approach–clearing aß fromthe brain–has progressed the furthest todate, advancing into human trials. Here,

3 D. J. Selkoe and D. Schenk, “Alzheimer’sDisease: Molecular Understanding PredictsAmyloid-based Therapeutics,” in Annual Reviewof Pharmacology and Toxicology, vol. 43, ed. A. K.Cho, T. F. Blaschke, P. A. Insel, and H. H. Loh(Palo Alto, Calif.: Annual Reviews, 2003),545–584.





the novel idea of immunizing patientswith the very peptide that builds up intheir brains has led to evidence in micethat one can ef½ciently clear aß plaqueswith aß antibodies. This has been ac-complished in two ways: either active-ly vaccinating the mice with syntheticaß so that they gradually generate theirown aß antibodies, or passively admin-istering laboratory-made aß antibodiesto them. When the active vaccinationapproach was initially tried in ad pa-tients, some 6 percent developed in-flammatory cell in½ltrates in the brain,or meningoencephalitis, and the trialstopped. The apparent reason for theinflammation: some patients had gen-erated specialized T-lymphocytes di-rected against the tail end of the aß pep-tide. Modi½ed active vaccines compris-ing the front end only have now beendesigned but not yet tested in humans.In the meantime, a phase 2 trial of pas-sive antibody administration is under-way in ad patients, with initial resultshoped for by late 2006.

In addition to the above approaches to the aß part of the ad equation, thereare strategies that attempt to target oth-er key steps in the disease cascade. Theseinclude oxidative injury to neurons, thebuild-up of tau as tangles, local inflam-matory changes, or a potential imbal-ance of certain metals such as copperand zinc in the ad brain. The use of cellculture and mouse models has assistedin the development of each of these po-tential therapies, followed in some casesby the initiation of clinical trials. At thiswriting, unequivocal evidence of suc-cessful slowing of the disease has notemerged, but hope runs high.

The advent of therapeutic agents thatslow and perhaps even prevent ad couldhave profound effects on the aged hu-man population, both on the individual

and the societal levels. A vaccinationstrategy for a noninfectious disease inlate life is unprecedented. Were a safevaccine or another aß-lowering thera-peutic such as a γ-secretase modulatorapproved, healthy people might avoidthe onset of Alzheimer-type cognitiveloss by undergoing the therapy in latemiddle age or perhaps even earlier. Suchan approach would have to include a for-mal, semiquantitative assessment of anindividual’s likelihood of developingad. Components of such a risk assess-ment may encompass a neurological ex-amination that includes cognitive test-ing, a detailed family history, a bloodscreen for genetic mutations known topredispose to ad or other dementias, a blood test for plasma aß levels, and aspecial brain imaging procedure like theemerging ‘amyloid scans’ that employan injected chemical agent to visualizeone’s cerebral aß burden. Such a multi-component assessment could assignindividuals a rough probability of devel-oping ad and perhaps other dementias,and those in moderate- or high-risk cate-gories could then be offered one of thepreventative agents envisioned above.

While such a combined diagnostic/therapeutic paradigm seems achievablewith time, it raises dif½cult new ques-tions. How can we administer such a relatively complex protocol to very large numbers of aging individuals?How will we pay for it? Will only rela-tively well-off individuals in developednations have access to it, at least for theforeseeable future? And how will wehandle the ethical challenges posed bywidespread testing for the genetic risk of a major, brain-destroying disease?

And there are other social implica-tions to ponder should a successful therapy for Alzheimer’s disease emergefrom current research. The prospect ofmany more people retaining most of

their cognitive functions into late lifeshould accelerate the current trend to-ward longer careers, potentially displac-ing younger workers. And because im-provements in the physical health ofoctogenarians will likely accompany theprevention of Alzheimer’s disease, andlater other dementias, we will need toexpand the availability of activities suchas driving, entertainment, tourism, and½nancial services. Healthy elders them-selves will presumably provide much ofthe labor required to deliver these serv-ices, but younger members of the workforce should also bene½t from these newopportunities.

Medical questions also abound. Couldwidespread access to effective therapyfor late-life cognitive failure actually in-crease longevity? Certainly, the averagelife expectancy at birth would rise mod-estly, at least in developed societies, butwill resolving dementia have a direct and measurable impact on the maximalage that humans achieve? Will manymore people live to 90 or 100 with theirmentation largely intact and then suc-cumb fairly rapidly to other causes ofmortality? And will other, currentlyinfrequent forms of cerebral deteriora-tion take the place of Alzheimer’s dis-ease as the primary cause of dementia,just as Alzheimer’s emerged stronglyafter the eradication of neurosyphilisand the more recent decline in strokes?

The looming prospect of solving Alz-heimer’s disease should be incorporatedinto the thinking of politicians, econo-mists, and all those concerned aboutplanning the future of our societies.While we will no doubt experience nu-merous ½ts and starts along the way, itappears increasingly likely that a worldwith less Alzheimer’s disease lies ahead.



The U.S. Social Security program provides an important ‘½rst pillar’ ofretirement income.1 Policymakers andthe media, therefore, pay considerableattention to the ½nancial viability ofthe program. Each year, the Social Se-curity trustees release a report that sum-marizes the ½nancial position of theSocial Security program. Among othermeasures, the report draws attention tothe program’s ‘crossover date’ (the yearthe program’s bene½t outlays will beginexceeding its tax receipts), the date of‘trust fund exhaustion,’ and the present

value of the program’s ½nancial short-falls over the next seventy-½ve years.2

These measures have two problems.First, they create a misleading impres-sion of the program’s ½nancial outlook.Second, they are biased against poten-tial reforms that could improve the pro-gram’s ½nances.

Fortunately, the trustees have recentlyadopted new accounting measures thatdeal with both problems. These meas-ures reveal an $11.1 trillion present-valueshortfall, which equals about 3.5 percentof the present value of all future taxablepayrolls. Unfortunately, because thesenew measures are buried in the trustees’report, they have received only scantconsideration from policymakers and


Jagadeesh Gokhale & Kent Smetters

Measuring Social Security’s ½nancial outlook within an aging society

Jagadeesh Gokhale is a Senior Fellow at the CatoInstitute. An expert on entitlement reform, laborproductivity and compensation, and U.S. ½scalpolicy, Gokhale has authored papers in the “Re-view of Economics and Statistics,” the “AmericanEconomic Review,” and the “Journal of PublicEconomics,” among others.

Kent Smetters is associate professor of insuranceand risk management at the Wharton School ofthe University of Pennsylvania. He has publishedarticles in the “American Economic Review,” the“Journal of Public Economics,” and the “Journalof Political Economy.”

© 2006 by Jagadeesh Gokhale & KentSmetters

1 Kent Smetters’s research was supported bythe U.S. Social Security Administration (ssa)through a grant in 2003 to the Michigan Retire-ment Research Consortium as part of the ssaRetirement Rese

book winter 2006 - american academy of arts and sciences...susan green½eld, david a. hollinger,...

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