Age-dependent changes in primary sensory neurons and nociceptors

Age-related loss of skin sensation increases the risk of burns, chronic wounds and falls, yet the cellular origins of this decline remain unknown. The dorsal-root-ganglion (DRG) houses more than a dozen molecularly distinct sensory-neuron subtypes, each tuned to specific thermal or mechanical forces. Whether aging compromises all of these subtypes equally, or selectively impairs the few that are critical for protective touch and pain, is a fundamental unanswered question. The proposed R21 will deliver the first systematic, cell-type–resolved map of how normal aging remodels peripheral sensory neurons. We will leverage a molecular-genetic toolkit we recently published, which enables subtype-specific labeling, to pursue sparse axonal reconstruction and in-vivo GCaMP imaging across a broad range of the distinct DRG sensory neuron subtype repertoire. We will pursue two exploratory aims. Aim 1: Quantify age-dependent morphological changes in the central and peripheral arbors of 13 transcriptionally defined DRG subtypes in young (2-3 mo) and old (>18 mo) male and female mice. Aim 2: Measure how aging alters the thermal- and mechanical-response profiles of the same subtypes using two-photon Ca²⁺ imaging while delivering precisely controlled quantitative mechanical or thermal force to the skin. These pilot studies are highly innovative because they unite large-scale single-cell transcriptomics with subtype-specific functional imaging, an experimental convergence that has only now become feasible. The work will generate a dataset that pinpoints which neuronal populations are structurally or functionally vulnerable (or resilient) to aging, providing immediate targets for mechanistic investigation or therapeutic protection. By establishing feasibility and delivering foundational knowledge, this project will catalyze a new phase of research on peripheral sensory aging, ultimately informing strategies to preserve touch and pain perception—and thereby independence and quality of life in our aging population. Project Number: 1R21AG101576-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Nikhil Sharma | Institution: COLUMBIA UNIVERSITY HEALTH SCIENCES, NEW YORK, NY | Award Amount: $450,200 | Activity Code: R21 | Study Section: Neurobiology of Pain and Itch Study Section [NPI] View on NIH RePORTER: https://reporter.nih.gov/project-details/11356656