A Glb1-2A-mCherry reporter monitors systemic aging and predicts lifespan in middle-aged mice

Abstract

The progressive decline of physiological function and the increased risk of age-related diseases challenge healthy aging. Multiple anti-aging manipulations, such as senolytics, have proven beneficial for health; however, the biomarkers that label in vivo senescence at systemic levels are lacking, thus hindering anti-aging applications. In this study, we generate a Glb1+/m‒Glb1-2A-mCherry (GAC) reporter allele at the Glb1 gene locus, which encodes lysosomal β-galactosidase—an enzyme elevated in tissues of old mice. A linear correlation between GAC signal and chronological age is established in a cohort of middle-aged (9 to 13 months) Glb1+/m mice. The high GAC signal is closely associated with cardiac hypertrophy and a shortened lifespan. Moreover, the GAC signal is exponentially increased in pathological senescence induced by bleomycin in the lung. Senolytic dasatinib and quercetin (D + Q) reduce GAC signal in bleomycin treated mice. Thus, the Glb1-2A-mCherry reporter mice monitors systemic aging and function decline, predicts lifespan, and may facilitate the understanding of aging mechanisms and help in the development of anti-aging interventions.

Biomarkers of aging

“…In humans, senescent cells accumulate in multiple tissues during aging. And a widely accepted biomarker for cellular senescence, SA-β-gal activity has been explored to monitor cellular aging in living mice (Sun et al, 2022a). p16…”

A rationally designed fluorescence probe achieves highly specific and long‐term detection of senescence in vitro and in vivo

“…β‐Gal is a typical glycoside hydrolase enzyme and is often used as a reporter enzyme to explore gene expression and regulation. Recently, Sun et al ( 2022 ) generated a Glb1‐2A‐mCherry (GAC) reporter allele at the Glb1 gene encoding lysosomal β‐Gal and used the reporter to successfully monitor systemic aging and predict lifespan in mice. However, transgenic approaches are still limited in early diagnosis, prevention, and treatment of aging‐related pathologies.…”

Senolytics enhance longevity inCaenorhabditis elegansby altering betaine metabolism

“…Evidence shows that aging influences various biological pathways, including metabolism, and leads to organ failure and even death. For aging assessment, the decline in memory and cognition, hypertrophic growth in cardiomyocytes, and facial recognition are commonly used [33]. However, the above methods are easily affected by the external environment and individual differences and cannot be used as universal detection methods.…”