The role of cellular senescence in ageing and endocrine disease

Abstract

With the ageing of the global population, interest is growing in the 'geroscience hypothesis', which posits that manipulation of fundamental ageing mechanisms will delay (in parallel) the appearance or severity of multiple chronic, non-communicable diseases, as these diseases share the same underlying risk factor - namely, ageing. In this context, cellular senescence has received considerable attention as a potential target in preventing or treating multiple age-related diseases and increasing healthspan. Here we review mechanisms of cellular senescence and approaches to target this pathway therapeutically using 'senolytic' drugs that kill senescent cells or inhibitors of the senescence-associated secretory phenotype (SASP). Furthermore, we highlight the evidence that cellular senescence has a causative role in multiple diseases associated with ageing. Finally, we focus on the role of cellular senescence in a number of endocrine diseases, including osteoporosis, metabolic syndrome and type 2 diabetes mellitus, as well as other endocrine conditions. Although much remains to be done, considerable preclinical evidence is now leading to the initiation of proof-of-concept clinical trials using senolytics for several endocrine and non-endocrine diseases.

Fig. 1 ∣. The central role of ageing in chronic diseases.

This figure shows examples of chronic non-communicable diseases that have ageing as one of the main risk factors. Reprinted with permission from REF., JCI.

Fig. 2 ∣. Nine fundamental hallmarks of ageing.

Nine fundamental physiological, cellular and molecular hallmarks of ageing that provide a useful framework for mechanistic studies. Reprinted with permission from REF., Elsevier.

Fig. 3 ∣. Causes and consequences of cellular senescence.

a ∣ Images of senescence-associated β-galactosidase (SA-βgal) staining of proliferating and senescent human preadipocytic cells. Bars represent 60 μm. b ∣ Different stimuli can induce cellular senescence. The phenotypes of senescent cells are cell type and context dependent; however, cells can develop a senescence-associated secretory phenotype (SASP), arrested proliferation and resistance to proapoptotic pathways through senescence-associated antiapoptotic pathways (SCAPs). The formation of senescent cells in response to damage has an important role in tumour suppression and is also necessary for tissue repair (for instance during wound healing). By contrast, the persistent presence of fairly small numbers of senescent cells can promote a protumorigenic milieu and impair the function of multiple tissues. ROS, reactive oxygen species.

Fig. 4 ∣. The effects of antiresorptive versus senolytic therapies on bone metabolism.

a ∣ Senescent cells accumulate in the bone microenvironment with ageing, where they increase bone resorption by osteoclasts and reduce bone formation by osteoblasts. Antiresorptive drugs inhibit or eliminate osteoclasts and decrease bone resorption. Owing to coupling between osteoclasts and osteoblasts in the bone remodelling cycle, bone formation is also reduced. b ∣ Senolytic therapy reduces the burden of senescent cells, which leads to a reduction in bone resorption with either increased (cortical bone) or maintained (trabecular bone) bone formation, resulting in a beneficial ‘uncoupling’ between bone resorption and bone formation. Dashed lines indicate a reduction in the adverse effects of senescent cells on osteoclasts, osteoblasts, and the coupling between osteoclasts and osteoblasts. Reprinted from REF., Springer Nature Limited.