Fight Aging!

INDY is a well-studied longevity-associated gene. Reduced INDY expression extends life in a number of short-lived laboratory species. Here, researchers argue that INDY inhibition could form the basis for osteoporosis treatments. Osteoporosis is the condition resulting from age-related loss of bone density. Bone is constantly remodeled by osteoblasts that build bone extracellular matrix and osteoclasts that destroy it. With advancing age, the activity of osteoclasts steadily outpaces the activity of osteoblasts. This occurs for a variety of reasons, and much of the research into osteoporosis is conducted in search of ways to restore the balance in some way.

Reduced expression of the plasma membrane citrate transporter SLC13A5, also known as INDY, has been linked to increased longevity and mitigated age-related cardiovascular and metabolic diseases. Citrate, a vital component of the tricarboxylic acid cycle, constitutes 1-5% of bone weight, binding to mineral apatite surfaces. Our previous research highlighted osteoblasts' specialized metabolic pathway facilitated by SLC13A5 regulating citrate uptake, production, and deposition within bones. Disrupting this pathway impairs bone mineralization in young mice.

New Mendelian randomization analysis using UK Biobank data indicated that SNPs linked to reduced SLC13A5 function lowered osteoporosis risk. Comparative studies of young (10 weeks) and middle-aged (52 weeks) osteocalcin-cre-driven osteoblast-specific Slc13a5 knockout mice (Slc13a5cKO) showed a sexual dimorphism: while middle-aged females exhibited improved elasticity, middle-aged males demonstrated enhanced bone strength due to reduced SLC13A5 function. These findings suggest reduced SLC13A5 function could attenuate age-related bone fragility, advocating for SLC13A5 inhibition as a potential osteoporosis treatment.

Link: https://doi.org/10.3390/metabo13121186