Geroprotectors and Skeletal Health: Beyond the Headlines

A New Paper, Discusses Rapamycin, Metformin, ACA, 17α-E2, GluN, Spermidine, Senolytics & more…


Similarly, less known but tested in the context of osteoarthritis (OA) is 17α-estradiol (17α-E2), a naturally occurring enantiomer of 17β-estradiol (17β-E2), yet appears to be non-feminizing due to minimal activation of classical oestrogen receptors, ERα and ERβ (Stout et al., 2016). It has been shown to extend lifespan in male mice (Harrison et al., 2014), ameliorate age-associated metabolic and inflammatory dysfunction (Stout et al., 2017) and improve male glucose tolerance across much of adult life (Garratt et al., 2017). When administered in later life it maintains body weight, with larger muscle mass and fibres, increased grip strength and coordination (Garratt et al., 2019). The metabolic improvements are sex-specific and influenced by gonadal hormones (Garratt et al., 2017). Little is known on the molecular basis of 17α-E2 on lifespan and healthspan. The metabolic improvements appear to be associated with enhanced hepatic mTORC2 signalling, increased AKT activity and phosphorylation of FOXO1 (Garratt et al., 2017), increased AMPKα and reduced mTOR complex 1 activity in visceral adipose tissue (Stout et al., 2017). These latter changes were not found in liver or quadriceps muscle (Stout et al., 2017).



Spermidine is also emerging for its geroprotective properties. It is a naturally occurring polyamine, and its concentration has been shown to decline with age in both males and females rat tissues and in erythrocytes (Jänne et al., 1964). Administration of spermidine extends lifespan in aged cells, C. Elegans , Drosophila (Eisenberg et al., 2009) and mice (Eisenberg et al., 2016) and it has been shown to improve some parameters of health. It increase B cell function in aged mice and humans (Zhang et al., 2019), cardiac function and arterial stiffness in aged mice (Eisenberg et al., 2016) and synapse ageing in drosophila (Maglione et al., 2019). Dhal salt sensitive rats fed high salt diet receiving spermidine showed reduced high blood pressure, delayed progression of heart failure and renal abnormalities seen in presence of hypertension (Eisenberg et al., 2016). In addition, administration of spermidine reduced the severity of liver lesions in a mouse model of liver cirrhosis (Yue et al., 2017) and of retinal ganglion cell death in a mouse model of optic nerve injury (Noro et al., 2015). In a community-based cohort study participants taking spermidine showed significant lower all-cause mortality (Kiechl et al., 2018). These effects seem to be the result of increased autophagy, mitophagy and mitochondrial biogenesis (Eisenberg et al., 2016). However, changes in other mechanisms associated with ageing have also been seen in presence of spermidine supplementation such as decreased histon H3 acetylation with possible consequences for gene expression (Eisenberg et al., 2009). Safety profile will require appropriate assessment in prospective studies as the results in animal models have been obtained using a wide range of doses, some of which may show toxicity when translating into humans.

Full Paper: