Cellular senescence and the aging brain

Abstract

Cellular senescence is a potent anti-cancer mechanism that arrests the proliferation of mitotically competent cells to prevent malignant transformation. Senescent cells accumulate with age in a variety of human and mouse tissues where they express a complex ‘senescence-associated secretory phenotype’ (SASP). The SASP includes many pro-inflammatory cytokines, chemokines, growth factors and proteases that have the potential to cause or exacerbate age-related pathology, both degenerative and hyperplastic. While cellular senescence in peripheral tissues has recently been linked to a number of age-related pathologies, its involvement in brain aging is just beginning to be explored. Recent data generated by several laboratories suggest both aging and age-related neurodegenerative diseases are accompanied by an increase in SASP-expressing senescent cells of non-neuronal origin in the brain. Moreover, this increase correlates with neurodegeneration. Senescent cells in the brain could therefore constitute novel therapeutic targets for treating age-related neuropathologies.

Redox control of senescence and age-related disease

“…Moreover, both IL-6 and IL-1β are independent predictors of diabetes [96]. In many prevalent neurodegenerative conditions including Alzheimer's Disease, brain tissue biopsies are present with increased levels of p16 INK4a - positive astrocytes, MMP-1 and IL-6 [99], [100]. Other prevalent pathologies which share several damaging SASP profiles including IL-6, IL-8, GM-CSF, MMP-1 [101] are chronic obstructive pulmonary disease (COPD), biliary cirrhosis and cholangitis [102], and osteoarthritis [103].…”

The impact of cerebrovascular aging on vascular cognitive impairment and dementia

“…Cellular senescence arrests the proliferation of mitotically competent cells, leading to permanent withdrawal from the cell cycle and is recognized as an example of evolutionary antagonistic pleiotropy (Campisi, 2003), preventing organs from developing cancer early in the reproductive years while promoting age-related phenotypes and pathologies (Chinta et al, 2015). In addition, senescent cells acquire a distinct phenotype known as the senescence-associated secretory phenotype and secrete multiple inflammatory cytokines, growth factors, and proteases that contribute to aging and the development of aging-related diseases (Chinta et al, 2015; Coppé et al, 2010).…”

“…In addition, senescent cells acquire a distinct phenotype known as the senescence-associated secretory phenotype and secrete multiple inflammatory cytokines, growth factors, and proteases that contribute to aging and the development of aging-related diseases (Chinta et al, 2015; Coppé et al, 2010). These detrimental factors are likely to function as paracrine mediators, altering neighboring cells and modulating the internal milieu.…”

Molecular pathology endpoints useful for aging studies

“…Circulating levels of the hormone dehydroepiandosterone (DHEA and its sulfate ester) decline with aging and there is a strong inverse association between DHEA(S) levels and risk of cardiovascular disease (Mannic et al, 2015). Senescent cells (identified as described above) accumulate in the central nervous system with aging and correlate with neurodegeneration (Chinta et al, 2015). Therefore, a combination of several common markers of age-related disease might be used to demonstrate extension of healthspan or effects of a therapeutic intervention targeting fundamental aging mechanisms.…”