Glutathione (GSH) & Aging

High Glutathione levels may prevent diseases of aging

The GSH antioxidant system is the body's powerhouse for diffusing

and disposing of free radicals that threaten cell, tissue and organ
damage, thus slowing the approach of aging.

John T. Pinto of Sloan Kettering Cancer Center in New York

proclaims GSH "The master antioxidant."

Jean Carper in her bestseller "Stop Aging Now!" highlights the same point: "You must get your levels
of GSH up if you want to keep your youth and live longer.

High blood levels of GSH predict good health as you age and a long life. Low levels predict early
disease and death."

These opinions result from convincing, fascinating research and experimentation. Age-specific
decreases in GSH are seen in all tissues, including liver, kidney, lung, heart, spleen and the brain.
Laboratory studies on the role of GSH in aging show GSH deficiency in all aging creatures, from
mosquitoes and houseflies to rats and mice.

Similar findings in humans indicate that elderly subjects bear increased risk of disease and
impairment. Blood-GSH concentrations in younger people (20-40 years) are 20 to 40% higher than in
those aged 60-80 years.

Studies by leading experts on aging (C.A. Lang, M. Julius and others) suggest that elevated GSH
levels give elderly individuals a physical, psychological and sociological advantage over those with
lower levels.

Researchers Mara Julius and Calvin Lang measured glutathione concentrations in community-based
individuals over the age of 60 years. They found that h igher glutathione levels corresponded to
lessened effects of aging and better general health.

Those with 20% greater blood GSH -levels experience about one-third the rate of arthritis, high blood
-pressure, heart disease, circulatory difficulties and other maladies.

Dr. Lang also looked at glutathione levels in age groups: 20-40, 40-60, 60-80 and 80-100 years.
The youngest group had acceptable levels but 14% of the 40-60 year olds and 53% of the 60-80 year
olds had critically low levels.

Interestingly, only 24% of the 80-100 year olds had low levels, perhaps explaining how they reached
such a ripe old age in the first place.

The Italians G. Paolisso and M.R. Tagliamonte went one step further, comparing adults under age 50
with those over 50. Both the GSH and antioxidant function were depressed in the older group.

However, those over 100 years old had higher GSH levels than the other over-50 group. Again,
this may explain their unusual longevity.
Several researchers over the years have also shown that life span can be extended by restricting diet
and maintaining low body weight.

No satisfactory explanation has emerged for this phenomenon, but some scientists have
demonstrated that glutathione levels rise in these longer-living individuals. They suggest that
glutathione may be involved in a molecular mechanism that contributes to longevity.

S.L. Nuttal and his British team published a revealing study in The Lancet, comparing GSH levels in
individuals of different ages and states of health. The healthy young had the highest levels, ahead of
the healthy elderly. The lowest levels were found in sick, elderly patients.

The results clearly showed that GSH levels fall as we age and as we become ill. The more severe the
illness, the more evident the decrease.

Back in the laboratory, scientists are trying to find out whether elevated GSH levels can actually extend
the life span. Aging-expert John Richie Jr. thinks that glutathione deficiency may be a biochemical
cause of the aging process.

In some of his experiments MgTC-a GSH promoting drug similar to OTC-was fed to mosquitoes.
GSH levels were found to be 50 to 100% higher, and life span was increased by almost 40%.

In another experiment, Diane Birt at the University of Nebraska fed hamsters the whey-protein
concentrate lactalbumin - a GSH-precursor. These animals also lived longer.

Interestingly, control hamsters on a diet including casein and cysteine, or methionine did not benefit.
In fact high cysteine loads proved harmful, showing how the bioactivity of these amino acids changes
when part of a larger protein, rather than free amino acids.

Dr. Gustavo Bounous and other researchers at McGill University demonstrated this anti-aging effect using a
natural product to elevate GSH levels. They fed mice a specially developed whey protein
isolate-later trademarked Immunocal - and compared their GSH levels and lifespan to mice on a standard diet.

Not only were the tissue GSH levels found to be higher, the mice fed un-denatured whey protein had
an average life span of 27 months (corresponding to a human age of 80 years) as compared to the con-
trol diet average of 21 months (human equivalent of 55 years). This is an astonishing increase of 30%.

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Antioxidant enzymes low in aging disease

NEW YORK Jun 08 (Reuters Health) -- People with progeria -- a rare, rapid aging disease -- have low
levels of the antioxidant enzymes believed to fight aging, researchers from the University of Iowa, Iowa
City, have found.

The results not only suggest that replacement of these enzymes may help treat people with progeria,
but they also provide insight into the normal aging process, he said.

People with progeria live on average to the age of 13. By the time they're 6 years old, they look
like they're 60 or 70. In addition to rapid aging, patients suffer delayed growth, a build up of fats and
cholesterol in the arteries, cardiovascular disease and other illnesses.
Studying progeria also enables researchers to examine the normal aging process. "We think normal
cell aging is caused by free radical damage," said Oberley. In their study, funded by the National
Institutes of Health, Oberley and colleagues compared skin cells of progeria patients with those of
healthy patients.

The researchers found that in cells from progeria patients, levels of three important antioxidant
enzymes were lower than those found in healthy cells.

Activity levels of the enzyme catalase were 50% lower than normal, while glutathione peroxidase activ-
ity was 70% less. In addition, the investigators note that progeria cells respond less well to the stress
of poor nutrition compared with healthy cells.

The results suggest two types of treatment for progeria, he said. For short-term treatment, existing
drugs that mimic the missing enzymes can be studied.

A long-term solution is to use genetic engineering to deliver genes coding for the enzymes into the
cells of progeria patients. This way, the genes will be able to produce the missing enzymes in the body.

Research in this area is at an early stage, but may be applicable to many diseases including cancer,
heart disease, stroke or diabetes, said Oberley.

SOURCE: Biochemical and Biophysical Research

Communications 1999;257:163-167.

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Articles and Research Publications on Glutathione and Aging

The Life Extension Protein that Fights Disease And Extends Lifespan
(LE Magazine January 1996) - By Will Brink

The influence of dietary whey protein on tissue glutathione and the diseases of aging Bounous G,
Gervais F, Amer V, Batist G, Gold P Montreal General Hospital Research Institute, Quebec. "Hence a
whey protein diet appears to enhance the liver and heart glutathione concentration in aging mice and
to increase longevity over a 6.3 month observation period. "

Relationships between the cellular glutathione level and in vitro life span of human diploid fibroblasts
Honda S, Matsuo M [Exp Gerontol 1988;23(2):81-6.] In order to examine the role of cellular glutathione
(GSH) in the in vitro aging of human diploid fibroblasts, we studied the effects of manipulated cellular
GSH levels on their in vitro life span. An increase in cellular GSH level was produced by the addition
of N-acetylcysteine (NAC), a carrier of cysteine across cell membranes, into the culture medium, while
a decrease in GSH level was produced by the addition of L-buthionine-(R,S)-sulfoximine (BSO),
a specific inhibitor of GSH synthetase. When the cells were serially subcultivated in a medium
containing NAC or BSO, their life spans were markedly extended or shortened, respectively, in
comparison to the life span of cells grown in a control medium. These results suggest that the cellular
GSH level is a determinant of the in vitro life span of human diploid cells.

Glutathione in human plasma: Decline in association with aging, age- related macular degeneration, and
diabetes Samiec PS, Drews-Botsch C, and others. [Free Radic Biol Med 1998 Mar 15;24(5):699-704.]
 Glutathione biosynthesis influences replicative longevity in
Saccharomyces cerevisiae Zandycke SM, Smart KA.
[ScientificWorldJournal. 2001 Jan 1;1(1 Suppl 3):133.]

The yeast Saccharomyces cerevisiae possesses a finite lifespan; the metric of which is the number of
times the cell divides and not its chronological age (1). The free radical theory of ageing postulates that
reactive oxygen species are causal factors in ageing (2). These species are capable of damaging DNA,
protein and lipids within the cell. For defence against these prooxidants, cells contain antioxidant mol-
ecule such as glutathione (GSH).

High blood glutathione levels accompany excellent physical

and mental health in women ages 60 to 103 years
Lang CA, Mills BJ, Lang HL, Liu MC, Usui WM, Richie J Jr, Mastropaolo W, Murrell SA. [J Lab Clin
Med. 2002 Dec;140(6):413-7.]

Earlier we found a high percentage of subnormal total glutathione (G(T)) levels in blood from elderly
subjects and patients with chronic diseases. These findings suggested a hypothesis that high levels of
G(T) in the blood occur in old persons who are in excellent physical and mental health. To this end,
we recruited 87 white women who ranged in age from 60 to 103 years and reported that they felt
healthy. Their health was verified with physical examinations, clinical chemistry profiles, psychosocial
assessments, and blood G(T) determinations. This evaluation was performed in three waves over a
5-year period. The values were compared with those from representative individuals in this region
and with normal national data. The results verified that these healthy subjects were in top physical and
mental health. We also found that subjects of all ages had very high blood G(T) levels in waves
I and II but only normal levels in wave III. These findings confirm that high blood G(T) concentrations
and excellent physical and mental health are characteristics of long-lived women.

Increased oxidative stress with aging reduces chondrocyte survival:

correlation with intracellular glutathione levels
Carlo MD Jr, Loeser RF. [Arthritis Rheum. 2003 Dec; 48(12): 3419-30.]

Cells depleted of intracellular glutathione were more susceptible to cell death induced by
SIN-1. These results provide evidence that increased oxidative stress with aging makes chondrocytes
more susceptible to oxidant-mediated cell death through the dysregulation of the glutathione
antioxidant system. This may represent an important contributing factor to the development of
osteoarthritis in older adults.