Ca2+ is a critical second messenger that is required for several cellular processes. Cytosolic Ca2+ (cCa2+)transients are shaped by the mitochondria due to the highly negative membrane potential and through themitochondrial calcium uniporter (MCU). Mitochondrial Ca2+ (mCa2+) is utilized by the matrix dehydrogenases formaintaining cellular bioenergetics. Reciprocally, dysregulated elevation of cCa2+ under conditions of stroke,ischemia/reperfusion injury drives mCa2+ overload that in turn leads to mitochondrial permeability transition poreopening that triggers necrotic cell death.

Identification of small molecules that extend mouse lifespan provides new insights intomechanisms of longevity determination in mammals, and may lay the groundwork for eventualanti-aging therapies in humans. The NIA Interventions Testing Program (ITP) evaluates agentsproposed to extend mouse lifespan by retardation of aging or postponement of late lifediseases.

SAMHD1, a mammalian member of the HD-domain hydrolase family of enzymes, catalyzes hydrolysis ofdeoxynucleotides triphosphates (dNTPs) to triphosphate and unphosphorylated nucleosides, which is thoughtto be the main pathway for controlled depletion of cellular dNTPs. Discoveries that SAMHD1 is an immunefactor that restricts retroviral replication in non-cycling immune cells and regulates interferon signaling revealedthat dNTP depletion may act as a defense mechanism of innate antiviral immunity.