PROJECT SUMMARY Telomeres, the repetitive DNA at the ends of chromosomes, shorten during every cell division except in very exceptional circumstances; in particular, rapid telomere elongation in the embryo is essential for ‘resetting’ telomere length. Long telomeres at birth protect genome stability and are associated with good health and increased longevity, while shorter telomeres are associated with age-related diseases and early mortality. We have discovered that embryos of obese females exhibit fundamental deficiencies during preimplantation development that result in offspring having shorter telomeres, providing an explanation for the increased risk of poor health and early mortality in adult children of obese women. Importantly, we have also determined that enhancement of mitochondrial bioenergetics in the oocytes of obese mothers restored the capacity for telomere lengthening during blastocyst formation. This indicates an important but previously unappreciated molecular link between mitochondria and telomeres and is the first evidence of a regulatory mechanism by which maternal physiology determines offspring aging and lifespan. The proposed work will define the molecular mechanisms by which telomeric DNA is extended during preimplantation embryogenesis, including in a clinically relevant nonhuman primate (NHP) model, establishing completely new concepts around the developmental programming of healthy aging. We will use cutting-edge micro-manipulation and molecular assessments of genome activation to determine how oocyte mitochondrial membrane potential is linked to embryo transcriptional reprogramming. Further, we will identify actionable therapeutic strategies for ensuring the integrity of these developmental processes in physiological contexts where they are defective. As maternal obesity rates continue to rise, understanding the impact of diet and obesity on embryo telomere reprogramming has important clinical ramifications because telomere length at birth is a well-understood determining factor for future disease risk. Identifying targets and therapeutic approaches to positively manipulate this biology will provide opportunities to protect essential molecular reprogramming events at conception and during early embryogenesis that ultimately improve lifetime health.