Families with exceptional longevity may inherit biological factors that favorably modulate aging processes and disease susceptibility. This inheritance has been demonstrated across generations in families with exceptional long-lived individuals. However, the genetic/biological pathways responsible for such phenotypes are still under active investigation. When studying genes that may be associated with human longevity, one must consider several approaches: 1. Infer that genes that modulate lifespan in lower species are conserved and have similar role in human aging. Such aging associated systems might have originated from a very early common ancestor. An example of such a lineage associated with aging is the insulin/insulin-like growth factor (IGF1) signaling pathway, which involves in many functions that are necessary for metabolism, growth, and fertility in animal models including fl ies, nematodes, and mammals. Mutations in genes that are part of this pathway in lower species led to signifi cant increases in lifespan. This observation, coupled with the homology to the human pathway, raised special interest in studying genetic alterations in the insulin/IGF1 signaling that may contribute to human's longevity. 2. Study genetic factors associated or causative to age-related diseases, namely cardiovascular disease, diabetes mellitus, cancer, and Alzheimer's disease. Because those diseases account for most age-dependent mortality, it was proposed that the more "perfect" (the one depleted from genotypes associated with age-related disease), the longer and healthier one would live. However, extremely old individuals that have genetic factors for these diseases seem to be protected from such diseases. Discovering such genomic mechanisms may provide another avenue to discover genetic protective mechanisms against known disease genotypes. 3. Discover protective genes in centenarians and their families. Centenarians and their family members seem to share certain biological protective factors that could be more easily discerned when looking beyond the centenarian index case. The survival advantage of these families is highly heritable, with siblings and offspring of centenarians also living long lives. Identifying which genes confer this unique advantage is also critical in understanding what controls human lifespan.