Beyond all empty promises of miracle drugs, it has been clear for decades that there is indeed a simple way to extend lifespan, though not one that most people who have a choice are particularly queuing up for: Eat less.

Calorie restriction extends lifespan in organisms from fungi to humans. But researchers still are working out the details of what happens on a cellular level when people swear off the well more than 2,000 calories that the average American now consumes daily and restrict themselves to something closer to two-thirds of that instead. Two recent papers report new findings on those mechanisms.

One class of enzymes clearly behind the lifespan increase is the sirtuins, a group of seven histone deacetylases that are activated by caloric restriction and control the aging process. In the Sept. 20, 2007, issue of Cell, researchers begin unraveling the specific role of mitochondrial sirtuins on cell survival.

Mitochondria are the energy powerhouses of cells, and in the Cell paper, researchers from Harvard Medical School, Weill College of Cornell University, the National Institute on Aging and Beth Israel Deaconess Medical Center probed the role of NAD+, a key cellular energy molecule, in the connection between eating less and living longer.

The authors showed that if levels of NAD+ remained normal in mitochondria, even when total cellular levels were depleted, that was sufficient to protect cells from apoptosis. The effect was dependent on having the mitochondrial sirtuins SIRT3 and SIRT4 in the mitochondria. In animals, caloric restriction activated the enzyme that synthesizes NAD+, providing the link between caloric restriction, mitochondrial sirtuins and cell survival.

The Cell data, Christoph Westphal told BioWorld Today, provided "the first functional evidence that the mitochondrion itself is the gatekeeper of cell survival. When mitochondria are functional, the cell can be rescued, even if there is almost no energy left in the rest of the cell."

Westphal is CEO of Sirtris Pharmaceuticals Inc., which he co-founded with Cell paper senior author David Sinclair. Sirtris is developing sirtuins for the treatment of diseases related to aging. The company's lead product, which is in Phase Ib trials for Type II diabetes, is a reformulation of the natural compound resveratrol that sports improved bioavailability, and targets the cytoplasmic sirtuin SIRT1.

Westphal said the company also has other compounds in the pipeline that are "a thousand times more effective than resveratrol, and completely chemically distinct."

The Cell research suggested that targeting mitochondrial sirtuins might be an additional way to unlock the therapeutic potential of the enzyme family. Westphal, who said "a lot of people believe that Type II diabetes is in large part a mitochondrial disorder," acknowledged that developing drugs to target mitochondria "is a higher hurdle" than targeting, for example, cell surface receptors, because drugs need to enter not just the cell, but also the mitochondrial subcompartment.

But, he added, drugs targeting the apoptotic proteins Bax and Bcl, as well as some benzodiazepines, target mitochondrial proteins. "It has been done multiple times before."

The Cell paper comes roughly a month after another group reported in the Proceedings of the National Academy of Sciences that at least in fruit flies, caloric restriction also appears to work by affecting p53 levels in insulin-producing cells, leading ultimately to down-regulation of a signaling pathway that is dampened by caloric restriction.

In the PNAS paper, which appeared in the Aug. 14, 2007, issue, scientists from Brown University followed up on a 2004 paper in which they had shown that decreasing expression of the tumor suppressor and DNA damage response protein p53 in the brains of fruit flies extended that species' lifespan, and is likely to be one of the mechanisms through which caloric restriction works.

In their new paper, the researchers narrowed down their findings by decreasing p53 in certain subsets of neurons instead of the entire fly brain. They found that the only subset of neurons that had an effect comparable to what they observed earlier was when they targeted insulin-producing cells - the fly equivalent of pancreatic beta cells. In those flies, caloric restriction had no additional effect on their lifespan, which suggested, the authors wrote in their paper, that that "reduction of [drosophila] p53 activity . . . may be a component of CR-dependent lifespan extension."

The authors suggested that p53 influences insulin secretion, which ultimately affects a signaling pathway in the drosophila fat body called the insulin/insulin-like growth factor signaling pathway.

Senior author Stephen Helfand, professor of biology at Brown, told BioWorld Today that the fat body has similarities to the mammalian liver as well as fat tissue. "The insect fat body . . . is the major site of storage and release of nutrients and detoxification of toxicants. It also has immune system function and probably many other things," he said.

As for the relationship between sirtuins and the insulin/insulin-like growth factor signaling pathway, Helfand said "there are likely a number of points" where the two pathways interact. Sirtuin, for example, affects insulin secretion in pancreatic beta cells - the same cells where decreasing p53 expression will increase fly lifespan.

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