We define Applied Healthspan Engineering as the use of behavioral, pharmacological, biomechanical, and regenerative means to maximize wellness with increasing chronological age and eventually overcome aging. Significant progress has been made in understanding the fundamental cell physiology of aging and age-related diseases. To catalyze discussion, we survey therapeutic approaches supported by current knowledge and chart a roadmap of those that in the near-term may be developed to extend the "healthspan".

Aging is characterized by gradual loss of function of cells, tissues and organs. Molecular mechanisms include accumulation of damaged molecules, and maladapted biochemical, genetic and epigenetic regulation. Cellular mechanisms include developmental drift, senescence, and loss of critical cells, especially progenitor and stem cells. Recent progress in molecular genetics has identified several molecular targets for possible intervention, including Target of Rapamycin (TOR)/FRAP1/Akt, and Sirtuins. Mutations in these pathways extend lifespan in yeast and some invertebrates. Alterations to these pathways may also play a role in lifespan extension by caloric restriction (CR) without malnutrition. CR delays the onset of aging and extends lifespan in diverse animal models including yeast, worms, flies, and laboratory rodents, although conclusive data for long-lived animals and primates does not yet exist. It is notable that increased longevity by CR is associated with increased vitality demonstrating a possible close link between potential therapeutic approaches that extend lifespan and healthspan.

Increased understanding of the physiology of mammalian/human diseases associated with, but probably secondary consequences of fundamental aging processes, provide a very good set of targets to extend healthspan today. These include the possible benefits of suppressing the increased activity of immune-mediated inflammatory pathways that drive increased incidence of age-associated diseases from arthritis, atherosclerosis and cancer to Alzheimer's disease. Another example is provided by recent studies that demonstrate the benefit of attenuating the biological effects of angiotensin II. Readily available drugs (e.g. ACE inhibitors and ARBs) that inhibit this pathway have been shown to extend the lives of rodents. Numerous studies support the use of low dose acetyl salicylic acid (ASA) to attenuate augmented platelet function that contributes to vascular disease. ASA at higher doses may be chemopreventive for colonic tumors. It is important to recognize that prophylactic alteration of the activity of disease-associated physiological pathways is not without the possibility of tradeoffs in which suppression of inflammation, for example, may reduce wound-healing and immunity. Even life-saving therapeutics may actually accelerate aging. For example, cancer chemotherapy may induce additional tumor mutations increasing drug resistance and contribute to development of subsequent secondary neoplasms. Chemotherapy may also cause the destruction of adult stem cell populations that help maintain the organism and delay aging.

The discussion will also include interventions that are based on simplistic or incorrect interpretations of the data, have not worked, are controversial or even fraudulent. For example, there is no doubt that oxidative damage accumulates with aging. However, anti-oxidants fail to augment lifespan in model organisms and may actually augment damage or curtail therapies under certain circumstances (e.g. chemotherapy). For example, Irvingia gabienesis, advertised as a solution to metabolic syndrome has proven difficult to reproduce.

What forms of therapy/intervention are possible today and in the future? We categorize potential therapies from most proximal and readily usable today to those that will require substantial advances in understanding aging or the technology itself:

A.Diet and exercise are easily and immediately accessible, although motivation may limit efficacy. Current data support the benefits of moderate exercise and well-balanced diet to increase healthspan, however significant extension of healthspan and longevity beyond genetic limitations is unlikely.

B.Elimination of exposure to stress and exogenous infection/inflammatory agents/stimuli are moderately controllable especially by vaccination in some cases. However, substantial progress will be required to eliminate chronic viral infections that apparently contribute to long term debilitation of the immune system. The continual evolution of pathogens and difficult development of new engineered substances make this approach problematic.

C.Nutritional supplementation and/or pharmacological interventions are interesting in that they may partially overcome genetic limitations by attenuating or stimulating key pathways involved in aging and aging-associated diseases. Presently, despite substantial