D. Hamerman, J. Zeleznik / Experimental Gerontology 36 (2001) 193±203

Experimental Gerontology 36 (2001) 193±203

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www.elsevier.nl/locate/expgero

Perspective

Translating basic aging research into geriatric health
care
D. Hamerman a,b,*, J. Zeleznik b
a

Resnick Gerontology Center, Albert Einstein College of Medicine and Monte®ore Medical Center,
111 East 210th Street, Bronx, NY 10467, USA
b
Department of Medicine, Division of Geriatrics, Albert Einstein College of Medicine,
Monte®ore Medical Center, Bronx, NY 10467, USA

Received 4 August 2000; received in revised form 8 September 2000; accepted 11 September 2000

Abstract
Aging processes are amenable to molecular genetic analyses. Two aspects of such research have
been selected for discussion in this paper because of current great interest and their relevance to
human aging. Studies on telomeres have revealed new insights on the control of cellular replicative
senescence and provided a means to extend the cell's life span during in vitro cultivation. Emerging
studies on genetic biomarkers have identi®ed genes that appear to be associated with longevity or
with risk factors for aging-related diseases, and raised considerations of ways to reduce disease
expression. An interchange between basic scientists and clinicians would encourage new thoughts on
the feasibility of translating these fundamental studies into interventions that promote healthier
longevity. q 2001 Elsevier Science Inc. All rights reserved.
Keywords: Translational research; Telomeres; Aging; Senescence; Disease

1. Introduction
Translating fundamental knowledge of cellular aging into geriatric health care requires
an interchange between basic scientists and clinicians (Hartwell, 1992; Manton et al., 1997).
The ultimate goal of this aspect of translation is to delay the onset or prevent the expression
of many age-related diseases (Vijg and Wei, 1995; Blumenthal, 1999; Wick and Xu, 1999).
This concept was expressed in a recent editorial: ªWe are convinced that studying basic,
age-related molecular processes at the cellular level will allow us to understand the development of age-related disease and devise new diagnostic, preventive and therapeutic
approachesº (Wick and Xu, 1999). Johnson et al. (1999) proposed that the aging process
* Corresponding author. Resnick Gerontology Center and Monte®ore Medical Center, 111 East 210th Street,
Bronx, NY 10467, USA. Tel.: 11-718-655-2542; fax: 11-718-882-7945.
0531-5565/01/$ - see front matter q 2001 Elsevier Science Inc. All rights reserved.
PII: S 0531-556 5(00)00200-X

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D. Hamerman, J. Zeleznik / Experimental Gerontology 36 (2001) 193±203

is ªamenable to molecular analyses and may be relatively simpleº. Gene expression impacts
on many areas of aging research such as stress responses and the generation of reactive
oxygen species generated by metabolism (Jazwinski, 1996; Martin et al., 1996; Dalton et al.,
1999; Fukagawa, 1999; Johnson et al., 1999); we have chosen to focus on two examples
where opportunities for potential translation to clinical practice may promote healthier
longevity: telomere functions that in¯uence cell aging and replication arrest, and genetic
biomarkers that may signify risk factors for human disease expression.
2. Basic aspects of aging, senescence, and disease
Geriatricians are seeking to formulate a ªnew gerontology that goes beyond the prior
preoccupation with age-related disease¼ to include a focus on senescence Ð the progressive nonpathological, biological, and physiological changes that occur with advanced ageº
(Rowe, 1997). However, the relationship between aging and senescence, at least at the
cellular level, remains uncertain. Human cells have a ®nite capacity to continue to replicate in vitro (Hay¯ick and Moorhead, 1961). One theory proposes that the ªaging process
that causes a cell to have a ®nite proliferative capacity, and its ability to enter the senescent
arrest state at the end of the life span, are separable properties¼ under separate genetic
Â
controlº (Stein and Dulõc, 1998). This is an intriguing but unproven hypothesis, and, at
present, it is generally accepted that the aging cell, replication-arrested at the G1 phase of
Â Â
the cell cycle, possesses a senescent phenotype (Campisi, 1997a; Berube et al., 1998;
Campisi, 1998; Ishikawa, 2000; Ran and Pereira-Smith, 2000). Nevertheless, the distinction between aging and senescence, if one can be made, becomes quite important and
potentially clinically relevant, in the light of interventions that can induce certain human
cells nearing the end of their replicative life span to continue replication.
One of the mechanisms for genetic control of the aging cell's capacity to continue to
replicate resides in telomeres, DNA at the ends of chromosomes that provide protection
against chromosome fusion, subsequent breakage (Greider, 1998; Urquidi et al., 2000),
and the activation of DNA damage checkpoints Ð all conditions that ªwreck havoc on the
genomeº (de Lange and Jacks, 1999). As somatic cells age, the telomeres shorten with
each successive cell division due to failure to renew a portion of the end of the telomere,
and to insuf®cient telomerase, an enzyme that replenishes telomere DNA (Harley and
Sherwood, 1997; Fossel, 1998; Greider, 1998; Colgin and Reddel, 1999; Holt and Shay,
1999; Cech, 2000). Linking telomere shortening to the triggering of senescence is the key
issue here (Sedivy, 1998). Apparently, a critical point is reached when shortened telomere
length activates multiple signaling mechanisms (Vojta and Barrett, 1995), particularly the
Rb, p16 INK4a, and p53 tumor suppressor pathways (Bringold and Serrano, 2000; Ishikawa,
2000; Young and Smith, 2000), which impose a limitation on the cell's capacity to
replicate; when replication ceases the cell enters a state of senescent growth arrest
Â Â
(Campisi, 1997a; Berube et al., 1998; Chin et al., 1999; Holt and Shay, 1999). Telomere
loss has been thought to be part of the ªdouble edged swordº (Campisi, 1997b) between
the anti-cancer effect of the senescent cell's growth arrest, and the multi-genetic factors
that in¯uence the cell to undergo malignant transformation (de Lange and DePinho, 1999).
However, in a number of human cell lines in vitro, including foreskin ®broblasts and

D. Hamerman, J. Zeleznik / Experimental Gerontology 36 (2001) 193±203

195

retinal pigment epithelial cells approaching the end of their replicative life span, introduction of telomerase into the cells extends telomere length and results in continued cell
replication (Bodnar et al., 1998; Vaziri and Benchimol, 1998; Jiang et al., 1999; Morales
et al., 1999), greatly expanding life span (Cech, 2000). These are very exciting results,
although they are not applicable to all human cell lines (Holt and Shay, 1999), nor
necessarily the key to extending human life span (Cech, 2000). It is important to note
that the experiments introducing telomerase into the human cells resulted in the cell's
continued proliferation without evidence of malignant transformation; only in the additional event that two oncogenes are inserted, or X-rays applied, does tumorigenesis occur
(Greenberg et al., 1999; Hahn et al., 1999a; Liu, 1999). Likewise, the introduction of SV
40 virus large T antigen, a viral oncogene, can extend the cell's replicative life span, but
the cells go through a crises in which most die and a few emerge as immortal (Holt and
Shay, 1999; Hubbard and Ozer, 1999; Lustig, 1999).
Extending the life span of a cell approaching replicative senescence by means of introducing telomerase could have potential clinical relevance in the event that in human
subjects organ damage occurs from accumulation of senescent cells. One of the important
characteristics of senescent cells at the end of their replicative life span is resistance to
apoptosis, or programmed cell death (Wang, 1995; Warner et al., 1997). Senescent cells
retained in aging organs are identi®ed by a histological stain that reveals their content of the
enzyme b-galactosidase (Campisi, 1997a), although the molecular basis for this ®nding is
not known. The accumulation in an organ of apparently senescent cells which fail to
replicate and fail to die may be a basis for decline in organ function (Campisi, 1997a;
Johnson et al., 1999; Kipling and Faragher, 1999), and in this sense senescent cells may
contribute to disease. Indeed, senescent cells display altered differentiated functions which
may be detrimental to tissues: depending on the cell type, there may be over-expression of
in¯ammatory cytokines, such as interleukin-1a, altered cell adhesion molecules, increased
metalloproteinases, and decreased metalloproteinase inhibitors (Campisi, 1998). All these
changes re¯ect a ªfairly dramatic switchº (Campisi, 1998) from matrix-producing to
matrix-degrading functions of the cell and may contribute to decline in organ function
and disease. Bodnar and coworkers (1998), who were among the ®rst researchers to introduce telomerase into presenescent human cells and demonstrate the cells' continuing replication, thought that such a procedure in elderly persons might be applicable to ªremedyº
certain examples of cellular senescence associated with organ damage in the skin (atrophy),
eye (macular degeneration), and blood vessels (atherogenesis).
There has been uncertainty and debate about the appropriateness of applying the results
of cell cultivation studies in vitro to cellular events in aging human organs. The recent
®ndings of Cristofalo et al. (1998) appeared to refute a central tenet of the long-held view
that the extent of cell replication in vitro was related to donor age; the authors used skin
biopsies from ªhealthyº donors and could not ®nd a correlation between cell culture
maximum life span and donor age. Even the shortened replicative span of ®broblasts
derived from Werner Syndrome subjects with premature aging now seems attributable
to mechanisms different from the traditional senescence of cells from control subjects
(Martin et al., 1999). Goyns and Lavery (2000) were skeptical about linking telomere
length to senescent replicative arrest, and by implication, the potential clinical relevance
of extending telomere length by telomerase introduction into cells. They noted that many

196

D. Hamerman, J. Zeleznik / Experimental Gerontology 36 (2001) 193±203

cells in the body do not proliferate regularly, may not lose telomere length, may not have
active telomerase, and may not reach the Hay¯ick limit (and thus senescent arrest). Still to
Â
be resolved, as mentioned earlier, is the view of Stein and Dulõc (1998) that distinct
genetic controls may determine the cell's ®nite proliferative capacity and senescent arrest.
Heterogeneity of cells in an aging organ is another aspect to be considered: there may be a
nondividing (senescent) and dividing population with altered metabolic functions
(Macieira-Coelho, 1995). Perhaps a minority of cells with shortened telomeres generate
a senescent signal (Sedivy, 1998). Thus, cells with both long and short replicative spans
and different metabolic expressions may exist in close proximity in vivo. Translation of
telomere biology would not conceptually be to prolong cell replication generally and
certainly not to extend human life span, even if these interventions were potentially
feasible. Rather, with the technology developed, human application might be designed
selectively for cells in certain organs, as, for example, for cardiac myocytes which diminish progressively during aging (Wei, 1992), or for cancer therapy, since telomerase levels
are elevated in the majority of malignant tumors (Holt and Shay, 1999). Inhibition of
telomerase in malignant cells might be a means to shorten their telomeres to critical
lengths (Hahn et al., 1999b), inducing replicative senescence and perhaps cell death due
to irreparable chromosome damage (Urquidi et al., 2000).
An approach to an in vivo demonstration of the relation of telomere length to aging
changes was observed in mice genetically engineered for telomerase de®ciency (Rudolph
et al., 1999). In the absence of telomerase, it took several generations until shortened
telomeres and genetic instability were manifested by a number of phenotypic ªagingº
changes: reduced life span, hair graying and alopecia, skin lesions at anatomical sites
exposed to chronic mechanical pressure ªsimilar to those seen in debilitated elderly
humansº that may re¯ect poor wound healing, impaired hematopoietic responses to stress,
a high cancer incidence, and decreased body weight. It was proposed that these ®ndings
ªdemonstrate a critical role for telomere length in the overall ®tness, reserve, and well-being
of the aging organismº (Rudolph et al., 1999). However, even in the presence of shortened
telomeres in these mice, a number of conditions prevalent in older human individuals were
not observed, including cataract formation, osteoporosis, glucose intolerance, and vascular
disease. Clearly, telomere function differs between species (Fossel, 1998), and in human
subjects telomere shortening is not invariable with aging. Thus, telomere length was not
signi®cantly different in esophageal mucosal cells derived from subjects age 21±100,
although in these cases telomeres were shorter than in cells from those under age 20 (Takubo
et al., 1999). Nor were telomeres shortened in dermal ®broblasts from healthy human
centenarians (Mondello et al., 1999), or in subjects with osteoporosis (Kveiborg et al.,
1999), or in those considered to have ªovarian agingº (Dorland et al., 1998). Thus, shortened
telomeres may be only one of many genetic and environmental determinants of cellular
aging (de Lange and DePinho, 1999; Johnson et al., 1999; Liu, 1999).
3. Genetic biomarkers
The emerging science of genetic biomarkers may tell us something about predisposition to diseases that become clinically manifest in older age (Wick, 2000), and

D. Hamerman, J. Zeleznik / Experimental Gerontology 36 (2001) 193±203

197

Table 1
Examples of genes that display polymorphisms associated with longevity or early morbidity (see text for discussion of alleles)
Gene

Designation

Functions

Reference

APOB
REN
SOD1
SOD2
THO
mt DNA
HLA-DR

Apolipoprotein B
Renin
Superoxide dismutase
Superoxide dismutase
Tyrosine hydroxylase
Mitochondral locus
Human leukocyte antigen

Lipid metabolism
Vascular tone
Scavenger of superoxide radicals
Scavenger of superoxide radicals
Catecholamines
Oxidative phosphorylation
Immune

ACE

Angiotensin converting enzyme

Vascular tone

APOE

Apolipoprotein E

Lipid metabolism

PAI-1

Plasminogen activator inhibitor

Clotting

Yashin et al., 2000
Yashin et al., 2000
Yashin et al., 2000
Yashin et al., 2000
Yashin et al., 2000
Yashin et al., 2000
Jazwinski, 1996;
È
Schachter, 1998;
Gonos, 2000
Jazwinski, 1996;
È
Schachter, 1998;
Gonos, 2000
Jazwinski, 1996;
È
Schachter, 1998;
Gonos, 2000
Jazwinski, 1996;
È
Schachter, 1998;
Gonos, 2000

represents an additional opportunity for collaboration between basic investigators and
È
clinicians (Vijg and Wei, 1995; Finch and Tanzi, 1997; Schachter, 1998; Miller, 1999;
Gonos, 2000; Yashin et al., 2000). A number of genetic variations Ð called alleles or
polymorphisms Ð have been identi®ed which appear to promote longevity or early
mortality. Table 1 lists some examples of the genes, drawn from the extensive
È
literature on the subject (reviewed by Jazwinski, 1996; Schachter, 1998; Gonos,
2000; Yashin et al., 2000). The allelic variants of four genes in particular Ð apolipoprotein E, angiotensin-converting enzyme, human leukocyte antigen, and plasminogen activator inhibitor Ð have been most intensively studied. Polymorphism in these
genes relates to outcomes associated with disease risk and shortened survival, or
longevity, especially manifest in centenarians who have ªescaped the major age-associated diseases and are in good mental and physical conditionº (Gonos, 2000). For
example, with respect to the HLA locus, DRw9 appears to predispose to autoimmune
È
diseases, whereas DR1, 7, 11 or 13 may be associated with longevity (Schachter,
1998; Gonos, 2000). The e4 allele of APOE appears to be a risk factor for coronary
artery disease and Alzheimer's disease, while the e2 variant may be protective and
È
associated with longevity (Jazwinski, 1996; Schachter, 1998; Gonos, 2000).
Alzheimer's disease is perhaps the area of gerontology that is emerging as most linked
to genetic biomarkers. Recent reviews by Tanzi (1999, 2000) set forth what he describes as
a genetic dichotomy model for Alzheimer's disease (AD), but in his view this might also
be relevant to other age-related disorders such as cardiovascular disease, cancer, and
diabetes. Early onset AD (under age 60) is caused by mutations in three different genes
Ð presenilin 1 (PSEN-1), presenilin 2 (PSEN-2), and the amyloid b protein precursor

198

D. Hamerman, J. Zeleznik / Experimental Gerontology 36 (2001) 193±203

(APP). These genetic defects are rare in the population, but their presence is almost 100%
associated with AD expression. On the other hand, and illustrating the dichotomy, late-life
expression of AD is associated with common population polymorphisms (CPP) distributed
throughout the human genome but imposing only a risk factor. Polymorphisms in two
genes Ð the APOE gene allele e4, as noted above, and a 2-macroglobulin (A2M), are
most widely appreciated as potential risk factors, but there are many other gene polymorphisms as well (Tanzi, 1999). More recently, Tanzi (2000) reviewed studies on interleukin-1 genes (IL-1A and IL-1B) where the dichotomy may not hold: polymorphism is
associated with risk for both late- and early-onset AD, possibly by promoting the in¯ammatory cascade of the disease process. Certainly, the implications of the ethical, legal, and
personal issues raised by genetic testing for AD (Post, 1994) must now be raised with even
more concern as such testing of these and other biomarkers becomes more widespread. In
this regard, the achievement of sequencing the entire human genome presents therapeutic
opportunities, according to Broder and Ventner (2000). They write ªin the not-too-distant
future, physicians may be able to use advanced, miniaturized technologies in their clinics
or of®ces to de®ne a patient's polymorphism pro®le in order to customize a diagnosis and
therapy to the speci®c patient's needsº.
In mice, gene expression pro®les of the aging process in skeletal muscle indicated only a
few increased or decreased expression levels as a function of age. The genes that showed
increased expression were mediators of stress responses and deleterious metabolic
processes (Lee et al., 1999). Of particular interest in terms of potential translation and
clinical relevance was their ®nding that deleterious aging-induced responses in the muscle
samples could be reduced by prior caloric restriction of these mice. Indeed, caloric restriction is an intervention that can extend life span in rodents (Weindruch and Sohal, 1997)
and may attenuate metabolic stress responses arising from the generation of oxidants and
the effects of glycemia and insulinemia. The bene®cial effects of stress reduction Ð what
Masoro (2000) called hormesis Ð arising from caloric restriction, is also associated with
increased heat shock protein (Heydari et al., 1993), diminished acute phase reactants
(Jazwinski, 1996; Ershler and Keller, 2000), and modulation of the hypothalamic-pituitary-adrenal axis (O'Connor et al., 2000).
4. Clinical means to improve health outcomes of older persons
Geriatricians have identi®ed health practices that appear to reduce disease expression
and promote ªsuccessful agingº (Rowe and Kahn, 1987). Behavior represents a means for
interaction of genes and the environment that may modulate an older individual's stress
responses by way of the neuroendocrine and immune systems Ð and, in favorable
circumstances, can promote healthy longevity (Mobbs, 1995). Adaptation seems to be
the key to favorable stress responses. Seeman et al. (1997) devised a score they called
allostatic load Ð by which they mean a person's ªstability through changeº Ð assessed
by a number of physiological measures and serum biochemical parameters. Low allostatic
scores re¯ected successful adaptation to stress and healthy functional capacity; conversely, high allostatic scores appeared to be correlated with failure of adaptation and adverse
health consequences. Individuals who age successfully appear to follow good lifestyle

D. Hamerman, J. Zeleznik / Experimental Gerontology 36 (2001) 193±203

199

habits, such as exercise, prudence in diet, social engagement, and active mental functioning (Rowe and Kahn, 1997). Many of these lifestyle habits extend disability-free time into
very late life (Vita et al., 1998; Leveille et al., 1999), and are part of the prescription for
preventive gerontology (Fries, 1997; Hazzard, 1997).
In clinical practice a number of therapeutic advances have led to reduced or delayed
later-life disease expression. The effects of cardiovascular diseases can be limited by
controlling systolic hypertension, high serum glycemic levels, and cholesterol elevation
(Rosen and Bilezikian, 1997). For osteoporosis prevention, the FDA has approved estrogen, alendronate Ð a bisphosphonate, and raloxifene Ð a selective estrogen receptor
modulator (SERM) (Fleisch, 1997; Cosman and Lindsay, 1999; Delmas, 1999) that slow
bone resorption and delay the transition of aging-related osteopenia to the disease osteoporosis with fractures; perhaps osteoporosis will become a ªdisease of the pastº (Rodan,
1994). Other therapeutic modalities under investigation that may reduce disease expression in aging persons include trials of selective cyclooxygenase-2 (COX-2) inhibitors that
appear to limit progression of precancerous colonic polyps (Lipsky, 1999; Shiff and
Rogas, 1999) and may decrease in¯ammatory neuronal loss that contributes to Alzheimer's disease (Aisen and Davis, 1997; Halliday et al., 2000), an aspect that IL-1 gene
polymorphism, cited above, may be critically linked with. Cytokine inhibitors also reduce
in¯ammatory changes in the joint that may progress to advanced rheumatoid arthritis
(Koopman and Moreland, 1998; Fox, 2000; Maini and Taylor, 2000), and may limit
rupture of the atheromatous plaque that results in coronary artery occlusion (Ridker et
al., 1997). Growth hormone secretagogues (Fuh and Vach, 1998) are an approach to
improve adverse changes in body composition associated with the somatopause (Lamberts
et al., 1997), and may delay the development of frailty (Hamerman, 1999).

5. Conclusions
We suggest a new orientation for health care that arises from basic and clinical studies
cited in this paper and the potential for scienti®c interchange: a focus on the evolution of
aging rather than on the alleviation of disease. Favorable personal health practices and
therapeutic interventions in late-life cited here can only go so far to improve healthier
longevity. Ultimately, means to apply the identi®cation of genetic biomarkers to predict
risk factors for disease expression, or to intervene selectively in the aging cell's replicative
processes and prolong them to delay senescent growth arrest or limit them to prevent
unrestricted growth, may be ways to achieve the translation of basic studies into the
clinical practices of molecular medicine for aging persons.

Acknowledgements
The authors are grateful to Judith Campisi, PhD, Department of Cancer Biology, Life
Sciences Division, Berkeley Laboratory, University of California, for helpful discussions.

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