Trained immunity links hematopoietic stem cell aging to aging-associated inflammation

Wei-Chieh Mu, Marine Barthez, Yufan Feng, Eric Verdin, Mihai G. Netea, Danica Chen

1. 01

   SIRT3 is highly expressed in hematopoietic stem cells and declines with age

2. 02

   SIRT3 suppresses the HSC response to aging that drives maladaptive trained immunity and chronic inflammation

3. 03

   HSC-specific SIRT3 overexpression ameliorated aging-associated HSC decline

4. 04

   Benefit extended to distant tissues: attenuated age-related declines in cognition and motility

5. 05

   Effect mediated by myeloid cells with modulated inflammatory programs

6. 06

   Relocates the origin of inflammaging upstream to an epigenetically trained stem-cell compartment

Study Design

Preclinical Study

Sample Size

Not reported

Study Duration

Aged-mouse study

Methodology

Genetic gain- and loss-of-function of SIRT3 in murine hematopoietic stem cells; myeloid lineage tracing and inflammatory profiling; behavioural and motor phenotyping of distant tissue function.

Limitations

Entirely murine and genetic. SIRT3 was manipulated by transgenic overexpression in HSCs — there is no small molecule, no human data, and no demonstration that NAD+ precursor supplementation (NMN, NR) raises HSC SIRT3 activity or reproduces any part of this phenotype. Do not read this as validation of sirtuin-directed supplements.