Loss of smelling is an early marker of aging and is associated with inflammation and DNA damage in C57BL/6J mice.

Olfactory dysfunction is a prevalent symptom and an early marker of age-related neurodegenerative diseases in humans, including Alzheimer's and Parkinson's Diseases. However, as olfactory dysfunction is also a common symptom of normal aging, it is important to identify associated behavioral and mechanistic changes that underlie olfactory dysfunction in nonpathological aging. In the present study, we systematically investigated age-related behavioral changes in four specific domains of olfaction and the molecular basis in C57BL/6J mice. Our results showed that selective loss of odor discrimination was the earliest smelling behavioral change with aging, followed by a decline in odor sensitivity and detection while odor habituation remained in old mice. Compared to behavioral changes related with cognitive and motor functions, smelling loss was among the earliest biomarkers of aging. During aging, metabolites related with oxidative stress, osmolytes, and infection became dysregulated in the olfactory bulb, and G protein coupled receptor-related signaling was significantly down regulated in olfactory bulbs of aged mice. Poly ADP-ribosylation levels, protein expression of DNA damage markers, and inflammation increased significantly in the olfactory bulb of older mice. Lower NAD+ levels were also detected. Supplementation of NAD+ through NR in water improved longevity and partially enhanced olfaction in aged mice. Our studies provide mechanistic and biological insights into the olfaction decline during aging and highlight the role of NAD+ for preserving smelling function and general health.

NEIL1 stimulates neurogenesis and suppresses neuroinflammation after stress.

Cellular exposure to ionizing radiation leads to oxidatively generated DNA damage, which has been implicated in neurodegenerative diseases. DNA damage is repaired by the evolutionarily conserved base excision repair (BER) system. Exposure of mice to ionizing radiation affects neurogenesis and neuroinflammation. However, the consequences of deficient DNA repair on adult neurogenesis and neuroinflammation are poorly understood despite their potential relevance for homeostasis. We previously reported that loss of NEIL1, an important DNA glycosylase involved in BER, is associated with deficiencies in spatial memory, olfaction, and protection against ischemic stroke in mice. Here, we show that Neil1-/- mice display an anxiety-mediated behavior in the open field test, a deficient recognitive memory in novel object recognition and increased neuroinflammatory response under basal conditions. Further, mice lacking NEIL1 have decreased neurogenesis and deficient resolution of neuroinflammation following gamma irradiation (IR)-induced stress compared to WT mice. Neil1-/- IR-exposed mice also exhibit increased DNA damage and apoptosis in the hippocampus. Interestingly, behavioral tests two weeks after IR showed impaired stress response in the Neil1-/- mice. Our data indicate that NEIL1 plays an important role in adult neurogenesis and in the resolution of neuroinflammation.