The Role of Senescent Cells in Age-Related Skeletal Diseases

Compelling evidence obtained from many studies in mice show that the accumulation of senescent cells with age is a major contributing factor in all of the common, inflammatory age-related conditions: cardiovascular disease, dementia, degeneration of bone tissue, and so forth. Senescent cells are created throughout life, mostly as somatic cells reach the Hayflick limit on replication, but accumulate in later life in large part because the immune system falters in its clearance of senescent cells. It still performs this function, but less efficiently, and the balance between creation and destruction of senescent cells tips to allow growing numbers of senescent cells to accumulate in tissues throughout the body. Senescent cells energetically secrete pro-inflammatory signals, and this signaling maintained over the long term is highly disruptive to tissue structure and function. It is a contributing cause of aging.

The animal data for the use of senolytic therapies to clear senescent cells is very compelling. Researchers have demonstrated rapid reversal of many aspects of aging and age-related conditions in mice. The results are impressive, larger, and more easily replicated than those produced by any other strategy to date, through epigenetic reprogramming may catch up as it becomes more widely assessed in the research community. There is a strong argument for greater investment in clinical trials for the proven first generation senolytic therapies, low-cost existing drugs and supplements such as the dasatinib and quercetin combination, that offer the near future possibility of additional years of healthy life for the entire elderly population. While many companies are working towards second generation senolytic therapies, it will be a long time yet before these treatments are in the clinic, or, once in the clinic, actually available at low cost for large numbers of people.

Cellular senescence in skeletal disease: mechanisms and treatment

Age-related musculoskeletal diseases such as osteoporosis (OP), osteoarthritis (OA), and intervertebral disc degeneration (IDD) critically affect the motor functions and quality of life of elderly individuals. Unfortunately, although various drugs, (such as bisphosphonates, recombinant human parathyroid hormone, denosumab for OP, and paracetamol for OA), have been approved for use, their benefits are limited due to side effects or the poor overall health of elderly individuals. Aging involves complex mechanisms, including genetic mutations, telomere shortening, epigenetic alterations, protein deformation, mitochondrial damage, and cellular senescence, which are responsible for the onset of age-related diseases. Thus, investigating and manipulating the mechanisms underlying aging are important future research goals. Among the fundamental mechanisms mentioned above, cellular senescence has received considerable attention in recent years.

Cellular senescence refers to the stable condition of cell cycle arrest, first described in the early 1960s. Senescent cells (SnCs) are produced in the early stages of embryonic development and accumulate with age. However, SnCs exert deleterious effects on tissues by secreting a plethora of inflammatory cytokines, chemokines, oxidative stress-related proteins, growth factors, and proteases, which is termed the senescence-associated secretory phenotype (SASP). Accumulated SnCs are a hallmark of aging and contribute to age-related diseases, including OP, diabetes, and Alzheimer's disease. Interestingly, SnCs have dual effects on tumour development, which may depend on the immune microenvironment or cell cycle stage, as cell cycle arrest is helpful for tumour suppression.

The skeletal system consists of bones, joints, cartilage tissues, and ligaments that work together to maintain homeostasis of the motor system and the internal environment. Bone remodeling occurs throughout life. Bone tissue comprises four types of cells: osteoblasts, osteoclasts, osteocytes, and osteoprogenitors. They undergo fundamental changes during the aging process. Senescent mesenchymal stem cells (MSCs) exhibit decreased osteogenesis and increased adipogenesis, moreover, senescent osteocytes or osteoclasts produce SASP. However, the underlying mechanisms by which SnCs and SASP regulate bone remodelling and induce disease are still under investigation. In this review, we summarise the role of senescence in the skeletal system, discuss its underlying mechanisms, and propose new strategies for treating age-related diseases by targeting senescence.