A gene called SIR2 is thought to control this process. Now, researchers at Harvard Medical School and UC Davis have discovered four cousins of the SIR2 gene that also extend lifespan, suggesting that the whole family of SIR2 genes is involved in controlling lifespan. The research indicates potential targets for developing drugs to lengthen life and prevent or treat aging-related diseases. The findings are reported July 28 in the advance online edition of Science. This discovery comes on the heels of the Harvard group's discovery of a molecule in red wine that extends the lifespan of every organism so far tested.

"We think these new Sir2 genes are as important as any longevity genes discovered so far," said molecular biologist David Sinclair, director of the Paul F. Glenn Laboratories for Aging Research at Harvard Medical School and co-author of the new study. "There is a growing realization from the aging field that we might finally understand how to control certain aspects of the aging process and one day have drugs that can fight some of the disabilities the process causes."

Sinclair's research group previously reported in the journal Nature the first genetic link between environmental stresses and longer life. Triggered by low salt, heat, or extreme calorie restriction, a yeast "master longevity regulator" called PNC1 stimulated Sir2 activity. This new work, led by Harvard graduate student Dudley Lamming, demonstrates that PNC1 regulates the whole SIR2 family of genes, suggesting that a human PNC1 gene might protect against diseases of aging such as cancer, heart disease and diabetes.

hms.harvard/

At this point, Tat must be chemically modified before it can encourage transcription of more HIV, and random thermal fluctuations in the cell can influence if and when these chemical modifications take place.

Because of Tat's positive-feedback loop, "these fluctuations can be amplified and can lead to very different qualitative behaviors," said Arkin.

If the appropriate modifications take place, then the HIV genome is transcribed and the positive feedback loop kicks in. If these Tat modifications don't happen, then HIV ceases to be expressed, and the cell can then possibly enter a latent state.

The significance of fluctuations in expression are dependent on HIV being expressed at a low level in the cell initially, Arkin said. Commonly, it's only when just a few molecules are interacting with each other that random fluctuations can have such a large effect on eventual outcome, he explained.

The researchers hope that understanding the molecular basis of HIV latency will lead to new treatments to slow or stop progression to AIDS. For example, Arkin suggested, the analysis implies that it might be effective to target the chemical modifications that Tat must undergo before it allows more HIV to be made. "When you quantify things and dissect them at this level, it gives you ways of exploring where your most vulnerable places might be."

Commenting on the work in a preview article published in the same issue of Cell, William J. Blake and James J. Collins of the Center for Biodynamics of Boston University, wrote: "The work of Weinberger et. al. represents an important step in moving from studies that elucidate the origins of stochasticity in gene expression to those that investigate the consequences of such molecular noise on cellular function. The authors [present] a scenario in which HIV-1 can hedge its bets by having an inherent ability to proceed either to latency or viral production. This intriguing notion still needs to be tested experimentally, and more broadly, much work remains to be done to understand the functional role that gene expression noise potentially plays in the progression of disease."

hhmi/