One of the HSL studies surveyed the entire human genome (all the genetic material in a living organism), called a genome-wide association study (GWAS), to look for common genetic variations in hereditary osteoporosis traits, such as bone mineral density.

We've examined nearly 100,000 genetic markers, says Douglas Kiel, M.D., M.P.H., director of medical research at IFAR and co-author of two of the papers, We're using this data and bone measurements over the years to see if bone mass is associated with certain genetic markers. We're looking for the genes for osteoporosis.

The other study, conducted by HSL investigators in collaboration with Boston University colleagues, took a GWAS approach to detecting genes related to longevity and aging traits. Two candidates are FOXO1a, which is associated with age at death, and PON1, which is associated with age at death and illness-free survival. These findings, if replicated in others studies, may help scientists understand better the mechanisms responsible for aging and, in turn, aid in health promotion and disease prevention.

The studies, published as part of a 17-paper supplement to the online, open-access journal BMC Medical Genetics, examined the genetic differences that potentially affect the risk for certain diseases, using data collected from the landmark Framingham Heart Study (FHS).

The studies evaluated DNA at 100,000 sites along the human genome where people are known to commonly differ. Researchers then looked for associations between the genotypes (the genetic makeup encoded in an individual's DNA) and hundreds of clinical phenotype measures (observable, physical characteristics) from nearly 60 years of FHS data, including biomarkers for cardiovascular disease, cancer, osteoporosis, longevity and aging, and renal and endocrine function, among others.

In addition to BMC Medical Genetics, the results of the studies are also available through an online database of genotypes and phenotypes (view/ncbi.nlm.nih/dbgap), which provides a number of electronic enhancements for viewing and examining the data, such as enabling users to drill down for precise details on all associations and allowing the data to be explored in the context of other National Center for Biotechnology Information genomic resources.

It is important to remember, says David Karasik, Ph.D., an associate scientist at IFAR and co-author of the HSL papers, that we need to replicate our findings in other studies. We haven't found the genes for osteoporosis and aging, but we've generated a hypothesis for future work.

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"We're not sure yet what particular mechanism is activated by these increased levels of NAD, and as a result SIRT3 and SIRT4," says Sinclair, "but we do see that normal cell-suicide programs are noticeably attenuated. This is the first time ever that SIRT3 and SIRT4 have been linked to cell survival."

In fact, the mitochondria appear to be so essential to the cell's life that when all other energy sources inside the cell--including the nucleus--are wiped out, yet the mitochondria are kept intact and functional, the cell remains alive.

"Mitochondria are the guardians of cell survival," says Sinclair. "If we can keep boosting levels of NAD in the mitochondria, which in turn stimulates buckets more of SIRT3 and SIRT4, then for a period of time the cell really needs nothing else."

Sinclair and his colleagues have coined a phrase for this observation: the Mitochondrial Oasis Hypothesis.

SIRT3 and SIRT4 may now also be potential drug targets for diseases associated with aging. For example, in recent years scientists have become increasingly aware of the importance of mitochondrial function in treating diseases such as cancer, diabetes, and neurodegeneration.

"Theoretically, we can envision a small molecule that can increase levels of NAD, or SIRT3 and SIRT4 directly, in the mitochondria," says Sinclair. "Such a molecule could be used for many age-related diseases."

According to Suave of Cornell, "This study also highlights how advanced technological methods can help resolve fundamental biological questions in ways that were hard to achieve as recently as a few years ago."

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