Longevity medicines

[Guest guest]

Hi All,

The article described below has been described for its abstract, but the

relative

importance of various strategies to promote longevity seem worthy of

consideration

for excerpted sections that may be more relevant generally and in light of CR

specifically.

See the pdf-available article details below.

RN, Fossel M, Harman SM, Heward CB, Olshansky SJ, Perls TT, Rothman

DJ, Rothman SM, Warner HR, West MD, WE.

Is there an antiaging medicine?

J Gerontol A Biol Sci Med Sci. 2002 Sep;57(9):B333-8. Review.

PMID: 12196485

Abstract

In spite of considerable hype to the contrary, there is no convincing evidence

that

currently existing so-called " antiaging " remedies promoted by a variety of

companies

and other organizations can slow aging or increase longevity in humans.

Nevertheless, a variety of experiments with laboratory animals indicate that

aging

rates and life expectancy can be altered. Research going back to the 1930s has

shown

that caloric restriction (also called dietary restriction) extends life

expectancy

by 30–40% in experimental animals, presumably at least partially by delaying the

occurrence of age-dependent diseases. Mutations that decrease production of

insulin

growth factor I in laboratory mammals, and those that decrease insulin-like

signaling in nematodes and fruit flies, have increased life expectancy as well.

Other general strategies that appear promising include interventions that reduce

oxidative stress and/or increase resistance to stress; hormone and cell

replacement

therapies may also have value in dealing with specific age-related pathologies.

This

article reports the findings of a consensus workshop that discussed what is

known

about existing and future interventions to slow, stop, or reverse aging in

animals,

and how these might be applied to humans through future research.

.... What Is Antiaging Medicine?

.... Caloric Restriction

Extensive research on caloric restriction or dietary restriction has clearly

shown

that it is possible to retard the rate of aging and also extend both the life

expectancy and maximum life span of animals. Weindruch and Walford summarized

early

research in this field (1). Subsequent studies have served to confirm and extend

these findings, and to suggest possible mechanisms by which caloric restriction

may

alter biological aging (2)(3)(4)(5). Caloric restriction extends life expectancy

by

30% to 40% if initiated in early adulthood, and by about 20% if initiated in

early

middle age. As long as a diet maintains adequate content of essential nutrients,

it

is not a " poor " diet, but a low-calorie, healthy diet. Presumably, caloric

restriction slows down the rate of aging at the same time as it delays the

occurrence of a wide range of age-dependent diseases and disabilities, such as

cancer, immune senescence, cognitive decline, loss of muscle strength, and

cataracts; it also reduces oxidative stress, and the damage it causes.

Genetic Manipulation

At least 15 different genetic manipulations induce life extension in organisms

such

as yeast, fruit flies, nematodes, and mice. Although many of these genes have

been

identified, it is not always obvious how the proteins coded by these genes are

involved in the regulation of longevity. However, there are similarities between

the

longevity genes identified in mice and those identified in invertebrates. For

example, growth hormone induces the production of insulin-like growth factor I

(IGF-I) in mammals. Mutations that decrease production, either of growth hormone

or

its receptor in mice, increase life expectancy, as do mutations that decrease

insulin-like signaling in nematodes and fruit flies. Thus, insulin and/or the

IGF-I

signaling pathway appear to be involved in longevity determination in a wide

range

of phylogenetically distant animal species (6). The results reported recently by

Flurkey and colleagues (7) suggest that growth hormone deficiency also delays

age-dependent collagen cross-linking and several age-sensitive indices of immune

system status. This demonstrates that a single gene can regulate life expectancy

and

the timing of both cellular and extracellular senescence in a mammal.

Antioxidant Intervention and Resistance to Stress

The relevance of a stress such as production of reactive oxygen species to life

expectancy, or to the rate of aging, is not known. Some epidemiological studies

have

suggested that dietary supplementation with vitamin E reduces the risk of cancer

(8)

and cardiovascular disease (9)(10)(11), but such observations are not universal

(12). Furthermore, the longevity-extending potential of vitamin E in animal

studies

remains equivocal (13). McCall and Frei (14) have concluded in a review that

" except

for supplemental vitamin E, and possibly vitamin C, being able to significantly

lower lipid oxidative damage in both smokers and nonsmokers, the current

evidence is

insufficient to conclude that antioxidant vitamin supplementation materially

reduces

oxidative damage in humans. " The only robust finding that a pharmacological

antioxidant can extend longevity in an animal model system is the report of

Melov

and colleagues (15) that EUK-134, a compound with both catalase and superoxide

dismutase activities, significantly extends longevity in nematodes.

Hormone Replacement Therapy

.... Estrogen Replacement Therapy

.... The Growth Hormone Paradox

.... Telomeres and Telomerase

.... Stem Cells and Cell Replacement Therapy

Gene manipulations possible in laboratory animals appear to have limited

potential

for direct application in humans, although they do provide insight into

important

biological factors in longevity determination in model systems. In contrast, the

potential of cell replacement therapy in reversing some of the adverse effects

of

aging appears to be substantial. Aging is accompanied by some loss of tissue

function, which is at least partially due to either the age-related loss of

cells

from the tissue or an increased proportion of dysfunctional cells. One example

is

the loss of specific types of neurons, which causes a variety of

neurodegenerative

diseases such as Parkinson's disease, Alzheimer's disease, and amyotrophic

lateral

sclerosis. Until the causes of this neuronal loss can be identified and

prevented,

cell replacement appears to be a theoretical alternative. Gage has reviewed the

current status of, and the potential for, use of stem cells for cell replacement

therapy in the central nervous system (42). Preliminary results using fetal stem

cells to restore function to paralyzed rat limbs have recently been reported

(43).

The recent isolation of nearly totipotent cells, such as human embryonic stem

(ES)

cells, offers an even greater range of opportunities (44). These cells express

telomerase and appear to maintain an immortal phenotype even after extended

culture

in vitro. Cells and tissues derived from such cultures may provide the unique

advantage of possessing a large replicative capacity and broad differentiation

potential. An example of the utility of this approach is that myocardial

precursors

derived from mouse ES cells appear to graft into mature myocardium, apparently

forming gap junctions with the neighboring myocardial cells and beating in

synchrony

(45). Such strategies for transplantation in the heart may eventually lead to

novel

therapies for arrhythmias and even the restoration of heart function following

ischemia or heart failure. More significantly, the replicative immortality and

undifferentiated state of human ES cells may lead to targeted genetic

modifications

and subsequent differentiation into many medically relevant cell types.

However, it is important to note that formidable hurdles are yet to be overcome

(46). First, cells derived from established human ES cell lines will probably

not

prove to be immunologically compatible with most patients. This may be resolved

by

immunosuppressive therapy, genetic modification of the cells to reduce

immunogenicity, or possibly the creation of a chimeric immune system in the

patient

to induce tolerance. The recent discovery of cell reprogramming through nuclear

transfer offers a path to the reprogramming of a patient's cell, thereby

reverting

it to an autologous ES cell (47). This approach has the advantage that

immunocompatibility would likely result. In addition, telomeres are

reconstructed in

the process (48). However, the ethics of ES technology and the use of nuclear

transfer in medicine is currently a matter of intense national debate (49), and

implementation of the technology may be slowed by limitations imposed on

National

Institutes of Health funding for stem cell research. Finally, it remains to be

seen

whether such new tissue (even if it were autologous) would be adequately

vascularized and subsequently function appropriately in the patient.

How to Test Potential Interventions

On the basis of caloric restriction and other dietary and genetic intervention

results with animal models, one can now make a principled argument that further

research along well-defined lines could produce a rational testable strategy for

interventions that might slow aging and/or decrease vulnerability to

age-associated

diseases in people. ...

Conclusions

The term " antiaging " has often been used to refer to both basic and clinical

studies

in this research area, but antiaging has acquired a tarnished image in the

gerontological community (51). The workshop participants agreed that instead of

" antiaging " medicine, the term " longevity medicine " should be considered by the

scientific community, and that it should apply to all means that would extend

healthy life, including health promotion, disease prevention, diet, exercise,

and

cessation of tobacco use, as well as advanced medical care and new discoveries

that

result from basic research.

Al Pater, PhD; email: old542000@...

__________________________________

- PC Magazine Editors' Choice 2005

http://mail.