-Mapping the epigenetic signature of nutritional state and socioeconomic positioning early in life

-Mapping the trajectories of epigenetic signatures at different time points in life and defining their association with nutrition and socioeconomic positioning at the different time points

-Mapping association between epigenetic signatures early in life and throughout life and longevity, define the functional genomic circuitries affected by epigenetic programming early in life that affect longevity.

Our understanding of the process of aging has advanced dramatically in the last decade as a result of elegant genetic work in model organisms, yeast, nematodes and mice. Although the process of aging has its unique characteristics in different branches of the phylogenic tree, common rules have emerged that could now be translated and tested in humans. One of the first principles is the inverse relationship between calorie intake and longevity in organism from different branches of the phylogenic tree. The molecular pathways mediating this involve the insulin response pathway. The second principle is the discovery of the involvement of a class of NAD dependent histone deacetylases the Sirtuins in longevity. Although these HDACs have non-histone targets as well as histone targets the involvement of an HDAC enzyme, alludes to an epigenetic pathway. Indeed elegant genetic analysis by in yeast has linked Sir2 and chromatin modification at telomeres, Sir 2 opposes replicative aging in yeast by maintaining low H4K16 acetylation at telemore elements. Interestingly the activity of Sir2 is dependent and sensitive metabolite in the cell NAD+, thus connecting this epigenetic process with cellular metabolism. The third principle is that the process of aging involves a systemic deregulation of gene expression suggesting a system wide genome wide rearrangement of control of gene expression. Aging seems to represent itself as a component of the normal trajectory of development from conception to death. Longevity is not just determined by the normal process of aging but it is mainly delineated by susceptibility to common adult onset disease such as cardiovascular, metabolic, cancer and mental and cognitive decline. These diseases involve as well system-wide changes in gene expression that affect critical gene-expression circuitries. Animal work from our lab as well as other laboratories suggests that there is an early developmental origin to late onset disease. Thus, adverse exposures early in life will be memorized and appear as adult onset disease that will affect longevity and shorten the life span. Epidemiological data in humans strongly suggests that poverty early in life as well as metabolic disruptions such as nutritional restriction during gestation as well as poverty during the perinatal period increase vulnerability to adult onset diseases including obesity, cardiovascular disease and autoimmune disease.

The critical question is mechanism: How are these early life experiences memorized in the genome so that they trigger disease during adulthood? Indeed can some be triggered by life experiences in the previous generation(s)?