Cellular Senescence as a Therapeutic Target for Age-Related Diseases: A Review

Abstract

Life expectancy has increased substantially over the last few decades, leading to a worldwide increase in the prevalence and burden of aging-associated diseases. Recent evidence has proven that cellular senescence contributes substantially to the development of these disorders. Cellular senescence is a state of cell cycle arrest with suppressed apoptosis and concomitant secretion of multiple bioactive factors (the senescence-associated secretory phenotype-SASP) that plays a physiological role in embryonic development and healing processes. However, DNA damage and oxidative stress that occur during aging cause the accumulation of senescent cells, which through their SASP bring about deleterious effects on multiple organ and systemic functions. Ablation of senescent cells through genetic or pharmacological means leads to improved life span and health span in animal models, and preliminary evidence suggests it may also have a positive impact on human health. Thus, strategies to reduce or eliminate the burden of senescent cells or their products have the potential to impact multiple clinical outcomes with a single intervention. In this review, we touch upon the basics of cell senescence and summarize the current state of development of therapies against cell senescence for human use.

Keywords: Aging; Non-communicable diseases; Senescence; Senolytics; Therapeutics.

Fig. 1

Pathways leading from the DNA damage response (DDR) to cell senescence. E2F is a transcription factor that stimulates the transition from G1 to S phase of the cell cycle. The retinoblastoma protein (Rb) is normally complexed with E2F, inhibiting it and preventing mitosis. When Rb is phosphorylated by a cyclin-dependent kinase (CDK), it releases E2F and cell division ensues. DNA damage activates the ATM or ATR kinases, stabilizing p53 and subsequently stimulating the expression of the protein p21, which is an inhibitor of the cyclin-dependent kinase CDK2. When CDK2 is inhibited by p21 as a consequence of the DDR, Rb remains complexed with E2F, and the cell enters a state of apoptosis or senescence. The DDR also leads to enhanced expression of p16, which inactivates CDK4 and CDK6, also preventing Rb phosphorylation and cell cycle progression

Fig. 2

Triggers of cellular senescence

Fig. 3

Characteristics of senescent cells and the senescence-associated secretory phenotype (SASP). EGF epidermal growth factor, IGF insulin-like growth factor, GM-CSF granulocyte-macrophage colony-stimulating factor, IFN-γ interferon gamma, MIF macrophage migration inhibitory factor

Fig. 4

Functions of cellular senescence throughout the life span. DPS developmentally programmed senescence, SIPS stress-induced premature senescence, RS replicative senescence

Fig. 5

Mechanism for the inducible apoptosis of senescent cells in INK-ATTAC mice. Zygotic cells are transfected with a construct encoding an FKBP/Casp8 complex plus a green fluorescent protein, all under the control of the Ink4a/Arf promoter (active only in senescent cells). Administration of the dimerizer AP20187 leads to conformation of an active caspase-8 and selective apoptosis of senescent cells in the whole organism. FKBP FK506 binding protein, IRES internal ribosomal entry site, GFP green fluorescent protein

Fig. 6

Therapeutic strategies to counter the effects of senescent cells. IGF-1 insulin-like growth factor 1, ROS reactive oxygen species, SASP senescence-associated secretory phenotype, JAK/STAT Janus kinase/signal transducers and activators of transcription, HSP-90 heat-shock protein 90, FOXO forkhead box proteins O