Figure 1. Combinatorial anti-aging strategies: Good and bad directions. (A) Chronic inflammation (or inflamm-aging) is commonly viewed as a central feature in aging and aging-related diseases [6,7,43]. Accordingly, the benefits arising from the anti-inflammatory effects of either dietary interventions/DRM strategies or senolytics might be directly enhanced in combination with well-characterized anti-inflammatory drugs (e.g., aspirin, non-steroidal anti-inflammatory drugs [NSAIDs] or nordihydroguaiaretic acid) [44–49], which may even operate at the hypothalamus level to impede systemic inflammation-driven aging [50]. However, a new paradigm for the role of inflamm-aging and immunosenescence (an aging-related decline in immune parameters that often leads to subclinical accumulation of pro-inflammatory factors and inflamm-aging) in the aging process begins to suggest that successful aging and longevity can only occur when changes in inflamm-aging are balanced by compensatory anti-inflamm-aging mechanisms [51]. In such a scenario, in which the immune/inflammatory system is adapted/remodeled to provide the best possible anti-pathogen protection when the adaptive immune systems fails in the elderly/aged organisms, the preservation of such apparently detrimental changes may be needed for optimal healthspan/longevity. Therefore, the aforementioned combinations (generating exacerbated decreases of the two components of the immunosenescence/inflamm-aging duo) might cause potential harm in terms of immune response impairment to infections in aged individuals. (B) Because many of the aging-associated features that are reverted by partial cell reprogramming are related to senescence [25], and given that cellular reprogramming on its own has been shown to rejuvenate senescent cells [52], a combination of senolytic and reprogramming strategies might provide synergistic anti-aging effects. However, it should be noted that the presence of inflammatory factors such as interleukin-6 (IL-6) in response to injury-induced senescence promotes cellular plasticity and responsiveness of neighboring cells to in vivo reprogramming-like phenomena [23,24]. Indeed, specific pharmacological and genetic removal of senescent cells has been shown to impair in vivo reprogramming efficiency [53]. The routes, kinetics, and intensities that would distinguish between the beneficial and the harmful effects of senescence in terms of the inherent susceptibility of different cell and tissue types to cellular reprogramming remains an important direction for future studies. (C) The cellular epigenome landscape directs cell fate and reflects its health and biological age. Certain dietary interventions (e.g., ketogenic diets), by altering the availability of key regulators for chromatin-modifying enzymes (e.g., the histone deacetylases inhibitor β-hydroxybutyrate), may provide a direct link between metabolism and epigenomic remodeling to extend healthspan and longevity [54,55]. Given the ability of dietary interventions and DRMs to affect the epigenome [31,56–58] and to suppress the development of senescence [59–62], an intriguing possibility is that dietary, pharmacological, and behavioral strategies targeting nutrient-sensing pathways might synergistically interact with cellular reprogramming strategies to provide better anti-aging outcomes. Nonetheless, certain dietary interventions could promote enhanced stemness and tumorigenicity in specific stem cell compartments and differentiated cell types [63,64]. Interference with normal wound healing processes and potentiation of tumorigenesis and cancer progression might therefore occur after excessive perturbation of the epigenome plasticity, as a maladaptive response to a combination of metabolic manipulations and partial reprogramming.