Age-related changes to adipose tissue and peripheral neuropathy in genetically diverse HET3 mice differ by sex and are not mitigated by rapamycin longevity treatment

Jake W. Willows, Department of Neurological Surgery, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA.
Morganne Robinson, University of Maine, Orono, Maine, USA.
Zahra Alshahal, Department of Neurological Surgery, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA.
Samantha K. Morrison, Department of Neurological Surgery, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA.
Gargi Mishra, Department of Neurological Surgery, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA.
Harrison Cyr, University of Maine, Orono, Maine, USA.
Magdalena Blaszkiewicz, Department of Neurological Surgery, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA.
Gilian Gunsch, Department of Neurological Surgery, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA.
Sabrina DiPietro, Department of Neurological Surgery, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA.
Emma Paradie, Department of Neurological Surgery, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA.
Benjamin Tero, Maine Medical Center Research Institute, Scarborough, Maine, USA.
Anne Harrington, Maine Medical Center Research Institute, Scarborough, Maine, USA.
Larisa Ryzhova, Maine Medical Center Research Institute, Scarborough, Maine, USA.
Lucy Liaw, Maine Medical Center Research Institute, Scarborough, Maine, USA.Follow
Peter C. Reifsnyder, The Jackson Laboratory, Bar Harbor, Maine, USA.
David E. Harrison, The Jackson Laboratory, Bar Harbor, Maine, USA.
Kristy L. Townsend, Department of Neurological Surgery, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA.

Document Type

Article

Publication Date

2-16-2023

Institution/Department

MaineHealth Institute for Research

Journal Title

Aging Cell

Abstract

Neural communication between the brain and adipose tissues regulates energy expenditure and metabolism through modulation of adipose tissue functions. We have recently demonstrated that under pathophysiological conditions (obesity, diabetes, and aging), total subcutaneous white adipose tissue (scWAT) innervation is decreased ('adipose neuropathy'). With advanced age in the C57BL/6J mouse, small fiber peripheral nerve endings in adipose tissue die back, resulting in reduced contact with adipose-resident blood vessels and other cells. This vascular neuropathy and parenchymal neuropathy together likely pose a physiological challenge for tissue function. In the current work, we used the genetically diverse HET3 mouse model to investigate the incidence of peripheral neuropathy and adipose tissue dysregulation across several ages in both male and female mice. We also investigated the anti-aging treatment rapamycin, an mTOR inhibitor, as a means to prevent or reduce adipose neuropathy. We found that HET3 mice displayed a reduced neuropathy phenotype compared to inbred C56BL/6 J mice, indicating genetic contributions to this aging phenotype. Compared to female HET3 mice, male HET3 mice had worse neuropathic phenotypes by 62 weeks of age. Female HET3 mice appeared to have increased protection from neuropathy until advanced age (126 weeks), after reproductive senescence. We found that rapamycin overall had little impact on neuropathy measures, and actually worsened adipose tissue inflammation and fibrosis. Despite its success as a longevity treatment in mice, higher doses and longer delivery paradigms for rapamycin may lead to a disconnect between life span and beneficial health outcomes.

First Page

e13784

Link to Full Text

Share

COinS