Senescence-Associated Secretory Phenotype Proteins as a Biomarker of Aging

In today's open access research, the authors report on the generation of a biomarker of aging from the study of proteins secreted by senescent cells. Low cost assays that map closely to biological age, the burden of damage, are a potentially useful tool for research and development of rejuvenation therapies. This biomarker is likely not general enough for that role; the accumulation of senescent cells with age in tissues throughout the body is just one of a number of mechanisms important in degenerative aging. It is always good to have further evidence that senescent cells are important in aging, to add to the very compelling animal studies that demonstrate rejuvenation when senescent cells are selectively destroyed, but an assay that reflects senescent cell burden is probably not helpful in the assessment of a candidate rejuvenation therapy that targets other mechanisms of aging.

Cells become senescent constantly, at all ages, largely somatic cells hitting the Hayflick limit on cellular replication. Cells also enter senescence when damaged, or in response to a toxic environment, or to aid in wound healing. That damaged cells become senescent helps to suppress cancer risk. This is all beneficial, so long as the senescent cells are promptly destroyed. A senescent cell releases into the surrounding environment a potent mix of molecules known as the senescence-associated secretory phenotype (SASP). The SASP rouses the immune system to inflammation, remodels tissue structure, and changes cell behavior, among other effects. This is beneficial in the short term, but becomes very damaging when sustained for the long-term. The lasting inflammation and disruption of tissue structure caused by senescent cells lingering in old tissues contributes meaningfully to the onset and progression of many age-related diseases.

The senescence-associated secretome as an indicator of age and medical risk

Aging is the strongest risk factor for the majority of chronic diseases. Recent scientific advances have led to the transformative hypothesis that interventions targeting the fundamental biology of aging have the potential to delay, if not prevent, the onset of age-associated conditions and extend human health span. Notably, there is now compelling evidence that cellular senescence, a state of stable growth arrest caused by diverse forms of cellular and molecular damage, contributes to aging, in part, through the senescence-associated secretory phenotype (SASP). Senescent cells accumulate with advancing age. Preclinical studies in rodents have established that transgenic strategies and drugs that selectively kill senescent cells improve numerous yet pathologically distinct conditions of aging.

Dramatic variability is inherent to aging. Many older adults of a given chronological age experience multiple chronic conditions and functional limitations, while paired-age counterparts may have low or no disease burden and comparatively greater functional independence. Advanced biological age may be linked to a greater burden of senescent cells in one or multiple organs. Core properties of senescent cells include upregulation of cyclin-dependent kinase inhibitors, morphological changes, activation of anti-apoptosis pathways, and a SASP composed of cytokines, chemokines, matrix remodeling proteins, and growth factors.

Senescent cell properties can be quantified in isolated tissues; however, this poses practical challenges for human application. Since the SASP is a key pathogenic feature of senescent cells, leveraging the circulating SASP as an indicator of systemic senescent cell burden may offer considerable utility. In clinical research, it can help identify persons who may be most responsive to emerging therapies and serve as surrogate endpoints in associated clinical trials. In clinical practice, SASP quantification may identify persons of advanced biological age and guide clinical decision making. We hypothesize that SASP abundance may be associated with chronological aging and accelerated biological aging.

We tested whether circulating concentrations of SASP proteins reflect age and medical risk in humans. We first screened senescent endothelial cells, fibroblasts, preadipocytes, epithelial cells, and myoblasts to identify candidates for human profiling. We then tested associations between circulating SASP proteins and clinical data from individuals throughout the life span and older adults undergoing surgery for prevalent but distinct age-related diseases. A community-based sample of people aged 20-90 years was studied to test associations between circulating SASP factors and chronological age. A subset of this cohort aged 60-90 years and separate cohorts of older adults undergoing surgery for severe aortic stenosis or ovarian cancer were studied to assess relationships between circulating concentrations of SASP proteins and biological age (determined by the accumulation of age-related health deficits) and/or postsurgical outcomes.

We showed that SASP proteins were positively associated with age, frailty, and adverse postsurgery outcomes. A panel of 7 SASP factors composed of growth differentiation factor 15 (GDF15), TNF receptor superfamily member 6 (FAS), osteopontin (OPN), TNF receptor 1 (TNFR1), ACTIVIN A, chemokine (C-C motif) ligand 3 (CCL3), and IL-15 predicted adverse events markedly better than a single SASP protein or age. Our findings suggest that the circulating SASP may serve as a clinically useful candidate biomarker of age-related health and a powerful tool for interventional human studies.


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