R.A. Miller

3 . Gruebeck-Loebenstein B., Lechner H., Treib K.: Long-term invitro growth of human T cell clones: Can post-mitotic 'senes­cent' cell populations be defined? Int. A rch. lm munol , 104:232 -239, 1994.

4. Perillo N.L., Naeim F., Walford R.L., Effros RB.: The invitro senescence of human T lymphocytes: failure to divide isnot associated with a loss of cytolytic activity or memory T cellphenotype . Mech. Agein g Dev . 67: 173-185, 1993.

5 . Effros R.B., Boucher N., Porter V., Zhu x.,Spaulding c. Wal­ford R.L., Kronenberg M., Cohen D., Schachter F.: Decline inCD28 +T cells in centenarians and in long-term T cell culturesa possible cause for both in vivo and in vitro immunosenes­cence . Exp . Geron tol. 29: 601-609,1994.

6. Effros R.B., Zhu X., Walford R.L.: Stress response of senes­cent T lymphocytes: reduced hsp70 is independent of the pro­liferative block. J. Geron tol. 49 : B65-B7 0, 1994.

7. Vaziri H. , Schachter F., Uchida I., Wei L., Zhu X., Effros R,Cohen D., Harley c.:Loss of telomeric DNA during aging ofnormal and trisomy 21 human lympocytes. Am. J. Hum.Gen et. 52: 661-667, 1993.

8 . Harley C.B.: Telomere loss: mitotic clock or genetic time­bomb. Mut at. Res. 256: 271 , 1991.

9 . Miller R A.: Aging and the immune response. In: SchneiderE.L., Rowe J'w. (Eds.], Handbook 0/ the biology of aging,ed. 3. Academic Press, New York, 1990 , pp .157-180 .

10 . Effros R.B., Allsopp R., Chiu C-P., Wang L., Hirji K., Ville­ponteau B., West M., Giorgi J .: Lymphocyte replicativesenescence in AIDS: telomere loss in the expa nded CD28­CD8+ subset. (submitted for publication).

Gerontology as oncology

R.A. MillerDepartment of Pathology, Institute of Gerontology,and Ann Arbor DVA Medical Center, University ofMichigan, Ann Arbor, Michigan, U.S.A.

The most fundamental of the many challenges fac­ing experimental gerontologists is to determine the na­ture of the mechanism that controls the synchrony ofage-dependent pathophysiologic processes within aspecies, and leads to species-specific differences inthe rate of aging. The aging process - though variablein detail from person to person - is remarkably syn­chron ized within a species. An 80-year old who ex­hibited no loss of sight or hearing , no memory deficits,no arthritis, no signs of renal or card iovascular disor­ders, no decline in muscle and immune function , andno history of neoplastic disease would be distinctlyunusual, while a 20-year old who exhibited any ofthese conditions would be almost equally rare. One canimagine a hypothetical mammalian species in which athird of the individuals died around age 10 of onespecific disease (say cardiac failure), a second th ird

466 Aging Clin. Exp. Res., Vol. 7 , No.6

died around 20 of a second illness (e.g., neoplasia) ,while the remaining third died at 30 of a neurode­generative illness. Su ch species do not, however,evolve, and the risk of the most common disabling andlethal conditions increases exponentially over mostof the adult life span. There is nothing intrinsic tothe structure of cells or tissues or organs that dictatesa working lifeof 2 or 20 or 60 years: the same patternof dysfunction that affects the eyes, skin, brain, muscles,and endocrine organs of 80-year-old humans is seen,in recognizable form, in 2.5-year-old mice and 25-year­old ho rses . Immune senescence, or myopenia , orhepatomas, or neurodegeneration, could in principleoccur in 3-year-old humans - these changes are, af­ter all, seen in 3-year-old rodents - but are in fact syn­chronously delayed until well into the post-reproductiveyears. Discovery of the process that leads, in long-livedspecies, to the parallel retardation of the vast spectrumof age-d ependent pathophysiologic changes is in asense the central goal of experimental gerontology.

A consideration of the comparative biology ofneoplasia puts this case in a particularly striking light.In genetically heterogeneous mice , the lifetime inci­dence of potentially lethal neoplasia is about 25%­50%, similar to the risk in humans. Since mice live, onaverage, only l/30th as long as humans, their risk pertime period is therefore 30-fold higher. Mice are also3000-fold smaller than people , and thus present3000-fold fewer 'target" cells at risk for the mutagenicand othe r stochastic processes that convert normalcells into malignant clones .

Thus, each mouse cell, on a given day, is 90 000­fold more likely than the corresponding human cell toinitiate (or complete) the oncogenic process. Evolutionof long-lived , large mammals has required the evolu­tion of anti-neoplastic defenses that reduce cancer riskby 90 000; without these defenses, no human wouldreach the age of puberty. It is in this sense thatgerontologists are oncologists: an understanding of thebasis for species-specific differences in aging ratewould , as a byproduct, provide critical insights intooncogenesis. The strongest risk factor for cancer is notage, but species.

Experimental work has begun to provide some in­sight into the factors that affect aging rate (and cancerincidence risk) within a species. Caloric restriction,discussed at length by oth er contributors to this sym­posium, provides strong support for a fundamental con­nection between aging rate and cancer causation, inthat effective restriction leads to parallel changes in neo­plasia incidence and non-neoplastic illnesses and dis­abilities (1). The age-adjusted incidenc e of both solidand hematopoietic tumors is diminished in mice bredselectively for high levels of early life humoral immunity

(2), and the "high-immune" mice have greatly in­creased mean and maximal life spans in comparison to"low-immune" mice bred in parallel. Interestingly,analysis of the genetic components of variation in lifespan and immunity in these selected mouse lines hassuggested that fixation of as few as 3 - 7 genetic locimay be sufficient to produce the dramatic differencesin longevity, immune function , and tumor incidence .Within the backcross populations that exhibited thegreatest variation in life span and immune function,those individual mice with the highest levels of immunefunction were also most likely to have long life span.Our own laboratory has also developed preliminaryev­idence that those mice whose immune systems seemto be aging most rapidly - as judged by the appear­ance of age-dependent T cell subsets - are mostlikely to succumb early in life to tumors (3). In our smallpilot study, the initial group of necropsies included atleast three distinct tumor types : lymphoblastic lym­phoma , follicular center cell lymphoma, and hepatic he­mangiosarcoma. Association between immune agingand life span, if confirmed by a larger study, might re­flect either control of immunosenescence and diseaseprocesses by an underlying timing mechanism, or theinvolvement of age-related immune decline in thepathogenesis of late life diseases including cancer.

There is essentially no information available todate concerning the genetic basis for differences in ag­ing rate among species. The demonstration that strik­ing differences in aging rate can evolve within a fewdozens of generations in the laboratory (2, 4 , 5), or ina few thousands of generations in the wild (6), suggeststhat this key question may prove to be experimentallyaccessible.

REFERENCES1. Weindruch R., Walford R.L.: Th e retardation of aging and

disease by dietary restriction. Charles C Thomas, Springfield,lL,1988.

2. Covelli V., Mouton D., Di Majo V., Bouthillier Y., BangraziC ,Mevel J.C , Rebessi 5 ., Doria G.. BiozziG.: Inheritance of im­mune responsiveness, life span . and disease incidence in in­terline crosses of mice selected for high or low multispecific an­tibody production . J. Im muno/. 142: 1224 -1234.1989 .

3 . Miller R.A., Turke P., Chrisp C , Ruger J., Luciano A., Pe­terson J., Chalmers K., Gorgas G., VanCise 5 .: Age-sensitiveT cell phenotypes covary in genetically hete rogeneous miceand predict early death from lymphoma. J. Gerontal. 49 :B255-B262 , 1994.

4 . Arking R.: Genetic analyses of aging processes in Drosophi­la. Exp. Aging Res. 14 : 125-135 , 1988 .

5 . Rose M.R.: Laboratory evolution of postponed senescence inDrosophila melanogaster. Evolu tion 38: 1004-1010,1984.

6 . Austad S .N.: Reta rded aging rate in an insular population ofopossums. J. Zoology 22 9 : 695-708, 1993.

Intervention in Aging IV

Oxidative damage of mitochondria:The effect of age and dietaryrestriction

B.P. YuDepartment of Physiology, The University of TexasHealth Science Center, San Antonio, Texas,U.S.A.

Recent studies of age-related alterations in biolog­ical function indicate that many cellular componentsundergo diverse forms of oxidative modifications dur­ing aging. Many scientists believe these oxidativechanges are likely due to the increased oxidativestress which occurs in organisms as they age (1). It hasbeen proven that oxidative stress can be exacerbatedby the combination of stresses resulting from a num­ber of biological sources, including unregulated freeradicals , lipid peroxidation , transition metals , andweakened antioxidant defense components, etc.

Quantitatively , mitochondria are the site of majorcellular free radical production. Various sources esti­mate that under normal physiological conditions ,about 1-4% of all oxygen taken up by mitochondria isconverted into a free radical (superoxide) when inap ­propriate one-electron transfer occurs during oxy­gen reduction. It is believed that this incessant pro­duction of free radicals could create conditions leadingto altered membrane structures and aberrant mem­brane functions. This may be the basis for the age-re­lated decline in mitochondrial function that has ledsome gerontologists to consider mitochondrial agingas the "biological clock" of cellular aging (2).

Mitochondrial DNA is at least 15 times more sus­ceptible to oxidative modification than nuclear DNA,and has less efficient repair mechanisms (3). Mito­chondrial DNA damage has been traced to mutationof specific mitochondrial genes. It has been hypoth­esized to lead to many abnormal cell functions , indi­cated by lowered state III respiration, increased stateN respiration, disturbed K+ and Cat " transport andimpaired protein synthesis (3). Thus , under increasedoxidative stress, biological consequences of mito­chondrial alterations are expected to be much greaterthan in other subcellular components. Some of themajor forms of oxidative alterations in mitochondriaare discussed in detail in the following sections.

Membrane lipid alterations

Substantial alterations in mitochondria during theaging process are documented through quantificationof oxidized mitochondrial lipids (4). Lipids, which

Aging Clin. Exp. Res., Vol. 7, No.6 467