Evading apoptosis in cancer

Roles of Apoptosis and Cellular Senescence in Cancer and Aging.

Cellular senescence (CS) is initially defined as an irreversible growth arrest of normal somatic cells, and has been proposed to contribute to tissue and organismal aging itself, and to be an intrinsic safeguard against tumor progression (1). SCs have been shown to have diverse phenotypes, including cellular flattening and hypertrophy, senescence-associated β-galactosidase activity (SAβG), senescence-associated secretory phenotype (SASP), resistance to apoptotic cell death, alterations in nuclear structure and senescence-associated heterochromatic foci (SAHF), mitochondrial expansion, and signaling events, including upregulation of cell cycle inhibitors and -pro-survival effectors (2). SCs accumulated in various tissues in mice with age, and comprised 5–40% of the total cells, depending on the tissue types (3). Although their number are relatively small in tissues, SCs can cause extensive dysfunction of the microenvironment and damage to surrounding cells and tissues, due to their pro-inflammatory senescence-associated secretory phenotype (SASP). Accumulating evidence suggests that CS plays an important role in diverse biological processes, such as embryonic development, diabetes, host immunity, wound healing, tissue renewal, as well as fibrosis, cardiovascular diseases, and cancer (4).

Since aging is one of major risk factors of human diseases, a variety of aging interventions have been developed to extend health span and to prevent or treat ARDs in in vitro and in vivoexperimental models. Caloric restriction (CR) is the only intervention shown to increase health span as well as to decrease the risk of ARDs in nonhuman primates (5). Recently, clinical trials of CR in non-obese humans revealed that a 15% lower calorie intake for 2 years delayed metabolism accompanied by reduced oxidative damage, suggesting that CR could also slow down the aging process in humans (6). Although CR can enhance healthy aging, the inconvenience of most subjects to maintain CR for a longtime limits its application. Therefore, caloric restriction mimetics (7), and calorie restriction diets or fasting-mimicking diets (8) have been proposed as alternatives. Elucidation of the mechanisms by which aging is regulated also suggested a variety of compounds and medicines, including sirtuin activators (9), AMP dependent protein kinase (AMPK) activators (10), mammalian target of rapamycin (mTOR) inhibitors (11), autophagy activators (12), that might be applicable for use in aging intervention. In addition, the use of geroprotectors, compounds and medicines that slow down aging, and thus lengthen the lifespan of model organisms has also been proposed (13). In present, a curated database of geroprotectors is available, and includes 259 compounds in 13 animal models from yeast to human, obtained from 2,408 literature (http://geroprotectors.org/). An old story tells the rejuvenation effects of young blood. Heterochronic parabiosis, in which an aged mouse and a young one were joined surgically, revealed that some factors in young blood, such as growth differentiation factor 11 with controversial reports and oxytocin enhanced tissue regeneration, and led to improvement of aging phenotypes (14). Similarly, transfusion of young serum also retarded age-related impairments in cognitive function and synaptic plasticity in aged mice (15, 16).

Although CS is one of hallmarks of aging (17), and accumulation of SCs with age has been suggested to be associated with aging and ARDs (18), direct evidence of a causal relationship between CS and aging or ARDs has only recently been validated in rodent models. Furthermore, senotherapeutics, have been implicated as novel strategies for aging intervention in applications designed to extend healthy aging and to prevent or treat ARDs.