Resveratrol targets what may be . . .

The Universal Cause of Aging
New light shed on the process by which resveratrol
significantly improves health and lifespan in mice
By Will Block

All truths are easy to understand once they are discovered; the point is to discover them.
— Galileo Galilei

n Roman mythology, Janus was the god of beginnings and endings. He is often portrayed by a head with two faces, each looking in opposite directions. Also thought of as the gate keeper, Janus was honored at the beginning of the harvest time, and at marriage, birth, and other beginnings. These include the important events that begin a person’s life. Janus also signifies the switch between primitive life and civilization, the countryside and the city, peace and war, and youth and adulthood. Altogether, Janus provides numerous insights for understanding the new beginnings and endings of a new theory of aging.

A research group led by sirtuin (sir-TOO-in) pioneer Dr. David Sinclair, Harvard Medical School professor of pathology, has shed light on the process by which resveratrol, a phytonutrient found in red wine and other foods, significantly improves health and lifespan in mice.1 In so doing, Sinclair and group have discovered what may be the universal cause of aging. They contend that this occurs when a specialized dual-role—Janus-like—enzyme known as SIRT1 (a sirtuin) shifts its attention, from keeping genetic peace by guarding and regulating which genes are switched on and off in a cell, to repairing double-strand DNA breaks caused by oxidative warfare. The essential discovery is paradoxical. When SIRT1 repeatedly rushes to fight DNA damage in the name of inhibiting aging, some of the genes it has formerly guarded express themselves in ways that are inimical to the integrity of the cell. The result is an acceleration of the aging process. Genomic instability and alterations in gene expression are hallmarks of aging.

This discovery bodes well for humans too, because it will enable researchers to figure how to best use sirtuin activators to enhance resistance to disease and prolong life.

New Relevancy for an Old Theory

Knowledge of this duality is not new. “For ten years, this entire phenomenon in yeast was considered to be relevant only to yeast,” said lead author of the study, Dr. Sinclair. “But we decided to test [if] this same process occurs in mammals.”2 And what they found is that, indeed, the same causality applies to single cell organisms such as yeast and multicellular organisms, including mammals. This represents the first time that such an evolutionarily aging mechanism—conserved for perhaps one billion years—has been identified between widely diverse organisms.

Moreover, this understanding suggests new ways to halt or reverse age-related disease, through the use of natural sirtuin activators, such as resveratrol, or drugs under development that possess some of the same characteristics. And while aging still remains a mystery to be solved, the new research allows important pieces of the puzzle to fall into place. Its hypothesis about how the sirtuin SIRT1 operates within a cell is strongly supported by the evidence, which goes a long way toward unveiling what (cringingly) may be thought of as the secrets of aging.

Guardians and Repair Managers

Within the nucleus of every cell of our bodies lies our chromosome, a six-foot long (if stretched out) double strand of DNA, containing about 20,000 genes. This is the blueprint for life. Under normal circumstances, each cell provides immediate access to a very limited number of genes specific to its type of cell (e.g., brain, blood, liver, bone, heart.)

As mice age, the researchers found, DNA damage accelerates and increasingly pulls the sirtuin SIRT1 away from its guardian posts. There, the first role of the SIRT1 sirtuin is to keep silent (i.e., suppress) all of the genes that are relevant to other types of cells, that it shouldn’t be accessing. SIRT1 does this by helping to preserve chromatin—the DNA packaging material—by tightening its wrappings and preventing the transcription machinery from expressing genes not specific to cellular needs, thus keeping them idle. This prevents genomic instability.

The second role of SIRT1 is to act as the cell’s repair manager, immediately mobilizing and relocating to the area of any genotoxic-stress damage breaks within the double-strand of DNA in the cell, such as that caused by UV or free radicals. The dilemma begins when SIRT1 moves from its guardian role to its repair managerial role, temporarily abandoning its first role as gene suppressor. Here lies the problem.

As the toll of aging continues, with the increased absence of SIRT1s from their guardian posts, deregulation of gene expression becomes persistent, and events spiral downwards. Chromatin looses its saran wrap-like grip and genes that should remain silent are activated. As sirtuins work overtime to extinguish damage around the genome, they no longer fulfill their guardian roles and the some of the unwrapped genes are permanently unsilenced (see Fig. 1).

Fig. 1. The Mechanism Behind the New Theory of Aging

SIRT1 genes are regulated by SIRT1 enzymes (on the left). When a double-strand break emergency occurs (on the right), the distress signal mobilizes SIRT1 enzymes, which migrate from their initial location and role as guardian, to the location of the double-strand break, where their role changes to that of repair manager. Although in the short term this migration (relocalization) response is temporary and beneficial, as continuous breaks occur the absence of SIRT1 enzymes lead to permanent transcriptional deregulation. The result of which is that genes that should be silenced are expressed. Moreover, when chronic double-strand breaks occur, genomic and epigenomic errors increase. The new theory finds that aging could be a consequence of the dilemma that causes transcriptional deregulation when genomic and epigenomic errors occur from double-strand breaks. Adapted from Vijg J, Maslov AY, Suh Y. Aging: a sirtuin shake-up? Cell 2008 Nov 28;135(5):797-8.

When the Parents Are Away

Analogously, when the guardians are away, genes can wake up and start “to party,” and in the process, play havoc and cause damage to the cell (think of teenagers left alone at home, by unwary parents on vacation). When the guardians SIRT1s are away and not maintaining their regulatory silencing of genes, the chromatin wrapping start to unravel, and the genes that are meant to stay silent in fact come to life. This cumulative damage is what we see in ourselves as normal aging. Or worse!

But if—continuing with the analogy—we could hire some surrogate parents to fill in for the vacationing parents, we could slow the aging process down by preventing the loss of guardian control. And indeed, we can do this by activating the SIRT1 genes to produce more SIRT1 proteins. With enough SIRT1s for both locations there might be fewer opportunities for cell damage . . . and the aging process might be slowed down.

Resveratrol Increases Longevity and Reduces Cancer

In their observations, the researchers found a direct correspondence between persistently active and unregulated mouse genes and age. The older the mice, the more unregulated were the genes.

“We then began wondering what would happen if we put more of the sirtuin back into the mice,” says Dr. Philipp Oberdoerffer, first author or the study, and a post-doctoral student in Sinclair’s lab at Harvard. “Our hypothesis was that with more sirtuins, DNA repair would be more efficient, and the mouse would maintain a youthful pattern gene expression into old age.”2

And their hypothesis proved correct. By two tokens, one which increased SIRT1 expression through the transgenic overexpression of SIRT1, and another which added the sirtuin activator resveratrol to the mice chow in the amount of 22.4 g/kg per day.* The results were significant and clear.


*To convert the dosages in this study to a human equivalent, we multiply by the standard mouse-to-human scaling factor, 0.081, which reflects the major differences between body surface area and metabolic rate between the two species. This gives 1.81 mg/kg per day, respectively, so for a 75-kg (165-lb) person, the amount becomes a daily dose of 136 mg per day. Since red wine contains about 1 mg of resveratrol per bottle, on average, it would take about 136 bottles per day to provide this amount. (Egad!) It can easily be obtained, however, through supplementation.


When oxidative stress was increased:

  • There was a loss of SIRT1-dependent silencing.
  • SIRT1 spent less time in its former protective role as gene guardian.
  • SIRT1 transcriptional deregulation was increased. This indicated that DNA damage caused by oxidative stress: 1) induced a change in SIRT1 distribution, affecting the expression of individual genes, and 2) that this effect can be suppressed by increasing SIRT1 levels.
  • SIRT1 was recruited to DNA double-strand breaks where its presence was required for efficient double-strand break repair and genomic stability.

When SIRT1 levels were increased:

  • Mice were protected from irradiation-induced cancer. Resveratrol-treated animals showed a 24% increase in survival and a 45% reduction in the frequency of fatal thymic lymphomas, about what would be expected from non-irradiated mice.
  • Transgenic mice, with overexpression of SIRT1, also benefited with increased survival of about 46% over controls and a reduced frequency of fatal thymic lymphomas of 45%, consistent with the resveratrol-fed mice.
  • SIRT1-unregulated genes were derepressed (reversed back to their guardian status) in the aging mouse brain and age-related changes were suppressed.

Re-emphasizing the most salient point of the paper, Dr. Oberdoerffer said, “According to this specific mechanism, while DNA damage exacerbates aging, the actual cause is not the DNA damage itself but the lack of gene regulation that results.” Continuing, “Lots of research has shown that this particular process of regulating gene activity, otherwise known as epigenetics, can be reversed—unlike actual mutations in DNA. We see here, through a proof-of-principal [sic] demonstration, that elements of aging can be reversed.”2

Resveratrol Exceeds the Advantages of Drugs

“It is remarkable that an aging mechanism found in yeast a decade ago, in which sirtuins redistribute with damage or aging, is also applicable to mammals,” says Dr. Leonard Guarente, Novartis Professor of Biology at MIT, who is not an author of the paper. “This should lead to new approaches to protect cells against the ravages of aging by finding drugs that can stabilize this redistribution of sirtuins over time.”2

That may eventually prove to be true, yet there are still a lot of advantages that resveratrol has over sirtuin drugs, which are still off in the distant future. On the upside, the power of resveratrol resides with many different effects, only a few of which have to do with its role as a sirtuin activator. Besides, sirtuin drugs may not hit the same high notes for people as resveratrol certainly does for mice, and by projection for humans. Resveratrol studies in humans are underway.


“We see here, through a proof-of-
principle demonstration, that
elements of aging can be reversed.”


In the bigger picture, sirtuins have an importance that goes beyond the newly discovered SIRT1 mechanism, according to Dr. Guarente. “The universal in aging we already know is sirtuins; they do so many things,” he says. Additionally, “The best way to approach this is to be able to trigger sirtuins so that you get all of the outputs and all of the benefits that they can bestow,” Furthermore, he notes, many of those outputs are ungoverned by the newly discovered mechanism.3

The Achilles Heal of Aging

“This is the first potentially fundamental, root cause of aging that we’ve found,” says Dr. Sinclair.3 “There may very well be others, but our finding that aging in a simple yeast cell is directly relevant to aging in mammals comes as a surprise.”3 “It was very exciting when we made the discovery, because it was so unexpected.”4

Referring to the new theory promulgated by the new study, David Sinclair is confident that his group may have uncovered a universal mechanism of aging. “Life, in general, has an Achilles heel,” a confident Sinclair reports, “and this is it.”4


“This is the first potentially
fundamental, root cause of
aging that we’ve found.”


Will the hypothesis gain widespread support? So far, based on the comments of others working in the field, it’s holding it own. Striking a note of caution to preclude the possibility that he might be wrong, Dr. Sinclair said he agreed that the case for sirtuin’s role in aging had not been proved. Yet, as per Dr. Sinclair, “We are careful not to say this is the cause of aging, but based on everything we know it’s not a bad hypothesis.”5

Taking It and Feeling Great

Dr. Sinclair has been taking large daily doses of resveratrol since he and others discovered five years ago that it activated sirtuin. “I’m still taking it, and I feel great,” he said, “but it’s too early to say if I’m young for my age.”5

Unified Theory of Aging

“The most exciting thing is that this work may unify in a single molecular pathway what we know about aging in different organisms such as yeast and mammals,” says Maria Blasco of the Spanish National Cancer Research Centre in Madrid, who works on mechanisms of cellular aging.6

New Beginnings for an Old Theory

Janus has been invoked for a great many theories across time, having been used for political, ethical, mathematical, philosophical, and even scientific hypotheses, conjectures, and speculations.7 Yet, for several reasons, Janus seems particularly appropriate for an aging theory. First of all, this recent discovery about how sirtuins work—as aging’s cause and cure—gives new life to an old theory that was running short on explanation, but is now brimming with insight. Secondly, the new theory is not only about new beginnings and new endings, but ironically—in its application to health and longevity—about reversing the aging process, the Holy Grail of our fondest dreams.

Human Equivalent Doses of Resveratrol

LEM0902_Table_thumb_305.gif
(click on thumbnail for full sized table)

*Calculated from Table 1: “Conversion of Animal Doses to Human Equivalent Doses (HED) Based on Body Surface Area,” available at http://www.fda.gov/cber/gdlns/dose.htm#v.

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References

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Will Block is the publisher and editorial director of Life Enhancement magazine.

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