The Search for
Soon after the dawn of humanity, people discovered, if they lived
long enough, that they experienced a gradual deterioration in their health as
they got old. Immediately after that, they realized they did not like it. From
that moment forward, humankind has been obsessed with finding ways to turn back
the clock or to at least stop it from advancing. Most of these have been
intuitive, such as maintaining a healthy lifestyle through diet and exercise.
However, we are never satisfied. This is the age of instant gratification, and
anyone would immediately invest in a company that could develop an anti-aging
pill—a fountain of youth in a bottle.
Although the exact causes of aging are still not clear, it is
believed to be the gradual wearing out over time of the body’s natu-ral ability
to maintain itself and repair damages. Logic dictates that natural selection
cannot help our longevity, because the difference between living to 70 and
living to 130 happens after the reproduc-tive years, so there is no selective
pressure for longevity.
It was discovered more than 70 years ago that calorie restriction
(CR) is associated with increased longevity in species as varied as yeast and
rodents. Restricting caloric intake by 30% compared to normal levels for the
species was shown to increase life span by 30% or more, and this is still the
only absolutely proven method of extending life span. In addition to the life
span extension, CR leads to a higher quality of life and forestalls many
diseases, such as cancer, diabetes, inflammation, and even neurodegenerative
diseases. Many mechanisms for this longevity increase have been suggested,
including general health benefits of weight reduction and specific improvements
in DNA management due to lower levels of oxidative compounds that are created
as by-products of metabolism. However, about 15 years ago researchers began to
pinpoint a family of genes in the yeast Saccharomyces
cerevisiae that seemed to be at the center of these increases in longevity
due to caloric restriction. The best characterized of these genes is SIR2, and evidence indicates that it is
the key regulator of the longev-ity mechanism, even though many individual
genes have been studied. In yeast and in roundworms, genetic manipulations that
doubled the number of SIR2 genes
increased life span by 50%. The protein product of the SIR2 gene is a histone deacetylase, but its function seems to be
more broad than just a piece of the replication puzzle.
Calorie restriction is a biological stressor like natural food
scarcity. Sir2 seems to be at the center of a generalized response to stress
that primes the organism for survival. The enzymes of this family are collectively
known as sirtuins, and many members
of the family are known. The mammalian version of the yeast gene is known as SIRT1, and it encodes the protein sirt1. As the figure shows, sirt1 in mammals
occupies a pivotal role in longevity through improved DNA stability, increased
repair and defense, prolonged cell survival, enhanced energy production and
use, and other coordinated stress responses. Mice that were engineered to lack SIRT1 do not show the longevity
increases associated with calorie restriction. Furthermore, doubling the number
of SIRT1 genes in an organism renders
it unresponsive to calorie restriction. Thus, it is now generally accepted that
calorie restriction promotes longevity by activation of sirtuins in general and
sirt1 in particular.
Of course, humans would prefer not to live a life of depri-vation
in order to reap the benefits of life span extension.
Therefore, the search for a stimulator of SIRT1 was on. One of the first compounds found that is a natural
activator of sirtuins is a small molecule called resveratrol, which is present in red wine and made by many plants
when stressed. Feeding resveratrol to yeast, worms, or flies, or placing them
on a calorie-restricted diet, extends their life spans about 30%, but only if
they possess the SIR2 gene.
Increased sirt1 in mice and rats allows some of the animals’ cells
to survive in the face of stress that would normally trigger their programmed
suicide. It does this by regulating several other key cellular proteins, such
as p53 . In addition, sirt1 is stimulated by increased ratios of NAD+/NADH, a
situation that arises when respiration is increased, as happens with fasting.
Thus, sirt1 is believed to act as both a sensor of nutrient availabil-ity and a
regulator of the liver’s response. Sirt1 has been linked to regulation of
insulin and insulin-like growth factor. As we saw, insulin is known to play an
important role in the general metabolic state of the organism.
Although we are decades away from seeing a true longevity pill, the studies referenced here indicate promise that such a compound can be found. As is often the case, it should be much easier to find the treasure when we are sure the treasure exists. The knowledge gained from the studies on sirtuins have been the first indication that we may yet be able to take control of our own longevity destiny, albeit sometime in the future.