# Long-term high-protein diet intake accelerates adipocyte senescence through macrophage CD38-mediated NAD+ depletion

## TL;DR

Eating a high-protein diet for a long time can speed up fat cell aging by reducing NAD+ levels through immune cell activity, leading to metabolic issues.

## Contribution

The study identifies macrophage CD38 as a key mediator of NAD+ depletion in adipocytes due to high-protein diets.

## Key findings

- Long-term high-protein diets cause NAD+ depletion and mitochondrial dysfunction in white adipose tissue.
- Macrophage CD38 upregulation depletes adipocyte NAD+ and accelerates cellular senescence.
- Restoring NAD+ levels or inhibiting CD38 activity alleviates metabolic issues from high-protein diets.

## Abstract

High-protein (HP) diets are widely adopted in Western societies for body-weight management; yet, they exacerbate senescence-associated metabolic deterioration, posing an unresolved pathophysiological conundrum. Here, we demonstrate that long-term HP intake mediates adipocyte-specific NAD+ depletion and mitochondrial dysfunction in white adipose tissue (WAT). Single-nucleus transcriptomic analyses revealed adipocyte-restricted senescence signatures in HP-fed mice. Mechanistically, HP intake triggers macrophage-specific upregulation of CD38 (a key NAD+ hydrolase), which depletes adipocyte NAD+ pools and thereby accelerates cellular senescence. Restoration of NAD+ levels, either via supplementation with NAD+ precursor or pharmacological inhibition of CD38 activity, alleviated the senescence-associated metabolic sequelae induced by HP diets. Our findings establish macrophage-adipocyte NAD+ crosstalk as a central axis linking dietary protein excess to WAT aging, providing actionable targets for the prevention and treatment of age-related metabolic disorders.

Image 1

•Long-term HP intake mediates adipocyte-specific NAD+ depletion and mitochondrial dysfunction in WAT.•Single-nucleus transcriptomic reveals adipocyte-restricted senescence signatures in HP-fed mice.•HP intake triggers macrophage-specific upregulation of CD38, which depletes adipocyte NAD+ pools and thereby accelerates cellular senescence.•Restoring NAD+ levels, via NAD+ precursor supplementation or pharmacological inhibition of CD38 activity, mitigates HP diet-induced senescence-associated metabolic sequelae.

Long-term HP intake mediates adipocyte-specific NAD+ depletion and mitochondrial dysfunction in WAT.

Single-nucleus transcriptomic reveals adipocyte-restricted senescence signatures in HP-fed mice.

HP intake triggers macrophage-specific upregulation of CD38, which depletes adipocyte NAD+ pools and thereby accelerates cellular senescence.

Restoring NAD+ levels, via NAD+ precursor supplementation or pharmacological inhibition of CD38 activity, mitigates HP diet-induced senescence-associated metabolic sequelae.