Paradoxes of senolytics

4289 AGING Senolytics are drugs that extend lifespan and delay some age-related diseases by killing senescent cells [14]. In fact, drug screens have identified a diverse group of drugs that are preferentially toxic to at least some senescent cells in some cellular models [2-9]. So far, however, their selectivity against senescent cells is modest and cell-type-specific [8-11]. Nevertheless, targeting senescent cells has been shown in animal models to prevent such age-related pathologies as emphysema [12], lung fibrosis [13-15], atherosclerosis [16, 17], osteoporosis [18], osteoarthritis [19-20], renal disease [21], intervertebral disk pathology [2], hepatic steatosis [22] and other age-related conditions [4, 7, 18, 23, 24]. In this editorial commentary, I want to draw your attention to the paradoxes associated with senolytics, which argue against the dogma that says aging is a functional decline caused by molecular damage. This dogma predicts that senolytics should accelerate aging. If aging is caused by loss of function, then killing senescent cells would be expected to accelerate aging, given that dead cells have no functionality at all. Instead, however, senolytics slow aging, which highlights a contradiction in the prevailing dogma. The theory of hyperfunctional aging [25-32] addresses this paradox. Killing senescent cells is beneficial because senescent cells are hyperfunctional [33]. The hypersecretory phenotype or Senescence-Associated Secretory Phenotype (SASP) is the best-known example of universal hyperfunction [34-36]. Most such hyperfunctions are tissue-specific. For example, senescent beta cells overproduce insulin [37] and thus activate mTOR in hepatocytes, adipocytes and other cells, causing their hyperfunction, which in turn leads to metabolic syndrome (obesity, hypertension, hyperlipidemia and hyperglycemia) and is also a risk factor for cancer [38-40]. SASP, hyperinsulinemia and obesity, hypertension, hyperlipidemia and hyperglycemia are all examples of absolute hyperfunction (an increase in functionality). In comparison, relative hyperfunction is an insufficient decrease of unneeded function. For example, protein synthesis decreases with aging, but that decrease is not sufficient [30]. In analogy, a car moving on the highway at 65 mph is not “hyperfunctional.” But if the car were to exit the highway and enter a residential driveway at only 60 mph it would be “hyperfunctional,” and stopping that car would likely prevent damage to other objects. www.aging‐us.com AGING 2018, Vol. 10, No. 12