Cellular senescence in chronic pain and aging

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Project Summary Chronic pain is a debilitating condition from which one in three Americans suffer, at a high cost to society. Aging is a major risk factor for the development of chronic pain with 50% of adults over the age of 65 suffering from at least one chronic pain condition. Unfortunately, it is not well understood why age is a risk factor for the development of pain conditions. Thus, there is an urgent need for basic research using aged animal models to examine the underlying interaction between age and pain and ultimately inform the development of tailored treatments for this specific population. As humans and animals age, senescent cells accumulate in many tissues throughout the body and disrupt tissue homeostasis by secreting factors that induce inflammation, known as senescence-associated secretory phenotype (SASP). Interestingly, several of these SASP factors are known pain-inducing cytokines that are released in the dorsal root ganglion (DRG), where primary sensory neuron cell bodies reside, and drive pain. Surprisingly, senescent cells have yet to be investigated within the pain circuit in aged mice, or even in young mice after peripheral nerve injury. We hypothesize that senescent cells; 1) are present in the pain circuit of aged mice, 2) further accumulate following nerve injury, and 3) contribute to chronic reflexive and affective pain responses through secretion of SASP factors. In support of our hypothesis, we have robust preliminary data demonstrating a 4-fold increase in senescent neurons in uninjured aged DRG compared to uninjured young DRG. Additionally, we demonstrate expression of the early senescence marker, p21, in injured (ATF3+) and uninjured (ATF3-) populations of Trpv1+ nociceptive neurons, suggesting paracrine induction of senescence. We localize the SASP factor and pain mediator, IL6, to these p21+ cells providing evidence that senescent cells are a cellular source of such factors in the pain circuit. Finally, we have preliminary data that indicate treatment with a senolytic drug improves spared nerve injury (SNI)-induced mechanical allodynia while maintaining overall sensory function in young adult and aged mice. Therefore, a potential mechanism underlying enhanced pain hypersensitivity following injury in aged mice may be the combination of age-related and injury- induced senescent cells. In this proposal, we aim to further characterize senescent cell induction following SNI by analyzing the co-expression of senescent markers within individual cells, determining their specific cellular identities, and quantifying SASP factor expression, at baseline (uninjured) and at acute and chronic post-injury time points in young and aged mice. Further, we will investigate the senescent cell contribution to neuronal hyperexcitability in vitro using 2-photon calcium imaging and electrophysiology, as well as in vivo using pain behavioral paradigms in aged mice compared to young adult mice after treatment with specific senolytic agents, which may selectively induce apoptosis of subtypes of senescent cells in the DRG. This research will be the first of its kind to investigate cellular senescence in a pre-clinical mouse model of neuropathic pain and has the potential to open a new therapeutic avenue, using senolytic agents, to alleviate pain.