Children with a genetic disease or birth defect are hospitalized at a younger age, stay longer, and have ahigher death rate than children hospitalized for other reasons. One in 33 infants born in the US has a birthdefect; the number one cause of infant mortality. Our long-term goal is to change these dire statistics bydelineating the mechanisms that reduce game quality by increasing mutagenesis in male gametes withincreasing age, i.e., the paternal age effect.

Proteostasis is an integral component of healthy aging. In most metazoans, protein quality declines during aging, resulting in accrual of damaged or self-aggregating cytotoxic proteins, linked to several age-associated diseases (e.g., Alzheimer's Disease, Parkinson's Disease) and pathology (e.g., sarcopenia, cataracts). The mouse-sized naked mole-rat [NMRs] lives ~5 times longer than expected based on body size, and despite detected high levels of oxidative damage even at a young age, maintain good health for most of their long lives.

Frailty is a geriatric syndrome which leads to poor health outcomes in older adults, such as falls, disability,hospitalization, institutionalization, and death. Due to the dramatic growth in the U.S. aging population and thehealth care costs associated with frailty (estimated at more than $18 billion per year), frailty is a major healthcare problem. There has been little research into potential pharmacologic interventions that would delay orreduce the incidence of frailty. Thus, the major goal of this study is to test metformin as a novel intervention forthe prevention of frailty.

A big concern has recently arisen regarding the safety of anesthesia in infants and children based on the profoundly increasing preclinical evidences in rodents and nonhuman primates that the commonly used anesthetics in clinic are neurotoxic to the developing brain and may cause long-term neurobehavioral abnormalities. Hence, the clinical relevance of anesthetic neurotoxicity as well as the development of biomarkers for early detection of anesthetic-induced neuronal injury is an urgent matter of public health.

Children with a genetic disease or birth defect are hospitalized at a younger age, stay longer, and have ahigher death rate than children hospitalized for other reasons. One in 33 infants born in the US has a birthdefect; the number one cause of infant mortality. Our long-term goal is to change these dire statistics bydelineating the mechanisms that reduce game quality by increasing mutagenesis in male gametes withincreasing age, i.e., the paternal age effect.

In response to RFA-AG-17-040, ?Short-term Measurements of Physical Resilience as aPredictor of Healthspan in Mice?, we propose testing primary fibroblast resilience with a panel ofdifferent cellular insults as a means to predict individual mouse longevity and healthspan. As outlinedby the funding announcement for this RFA, there is a need to develop these standardized tests foruse among the aging community to accelerate research towards revealing mechanisms that underlythe physiological decline of aging.