58 This temporal study showed that the counter-proteotoxic functions of IIS reduction are separable from its longevity effects, proposing that protection from toxic GW786034 protein aggregation can be achieved without lifespan

extension. Recently, we have found that HSF-1 also executes its longevity functions foremost during early development.60 The studies described in this review point to IIS reduction as an attractive Inhibitors,research,lifescience,medical avenue towards the development of novel neurodegeneration therapies. This theme suggests that IIS reduction by pharmacological agents (Figure 1) (I), will hyper-activate the transcription factors downstream of the insulin/IGF receptor (II) and increase the expression of protective target gene networks (III). Elevated expression of these gene networks will maintain functional proteostasis (IV), prevent toxic protein aggregation from occurring (V), and prevent the manifestation of neurodegenerative disorders

late in life (VI). This model calls for the development of specific IIS inhibitors and their evaluation as counter-neurodegeneration drugs. Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical One such drug, Psammaplysene A, has been tested in cell culture and in a fly model of proteotoxicity and was found to drive FOXO3a into the neuronal nuclei and to protect motor neurons and fly eyes from toxic protein aggregation.61 New IIS inhibitors are being developed, and their efficiency as novel counter-neurodegeneration drugs will be tested in the years to come. Figure 1 A model for the prevention of neurodegeneration by IIS reduction. Abbreviations: AD Alzheimer’s disease;

ALS amyotrophic lateral sclerosis; APP amyloid precursor protein; HD Huntington disease; HSF-1 heat-shock factor 1; IGF insulin-like growth factor; Igf1r insulin-like growth factor-1 Inhibitors,research,lifescience,medical receptor; IIS insulin/IGF signaling; PD Parkinson’s disease; polyQ polyglutamine; PS1 presenilin-1. Footnotes Conflict of interest: No potential conflict Inhibitors,research,lifescience,medical of interest relevant to this article was reported.
From the beginning of humanity, we have been seeking an explanation and consolation for the continuous physiological decline of aging. These days were well described in Ecclesiastes 12:1 Entinostat as “… and years arrive, about which you will say, I have no desire in them.” The significant increase in human longevity during the last century has created great sociological, economic, and mainly medical challenges. To answer these challenges, one must understand and directly control the mechanisms that determine the rate of aging. In essence, most accepted theories on the mechanism of aging, such as the “snowball,” “free radicals,” and “disposable soma,” share a common denominator in suggesting that improved body maintenance could extend life. Particularly important are increasing genome stability and preserving proper metabolism. One family of proteins that have been implicated in aging and the regulation of metabolism and genome stability are the sirtuins.