Longevity Pathways: HSF1 and FoxO Pathways, a New Therapeutic Target to Prevent Age-Related Diseases

Felipe      P. Perez; Syed      S. Moinuddin; Qurrat      ul ain Shamim; Dennis      J. Joseph; Jorge      Morisaki; Ximing      Zhou

Abstract

Modern medicine is directed towards the prevention, detection and cure of individual diseases. Yet, current medical models inadequately describe aging-associated diseases. We now know that failure in longevity pathways including oxidative stress, multisystem dysregulation, inflammation, sarcopenia, protein deposition and atherosclerosis are associated with age-related diseases. Such longevity pathways are potential targets for therapeutic intervention. Interventions in specific pathways have been shown to ameliorate and postpone the aging phenotype by activation of multiple genes. The strategy that we propose in this paper is to apply interventions simultaneously on complementary longevity pathways to achieve a synergistic result. For instance, aging is known to attenuate the HSF1 pathway leading to production of very toxic beta-amyloid fibrils. Consequently, the FoxO pathway is activated, resulting in the formation of less toxic high molecular weight aggregates as a defense mechanism. Thus the simultaneous upregulation of the HSF1 and FoxO pathways could potentially decrease protein deposition and proteotoxicity, thereby retarding or possibly preventing the onset of neurodegenerative diseases. Modulating these two pathways may also delay the onset of other age-related pathologies including cognitive decline, cancer, diabetes and cardiovascular disease due to its multi-gene effect. In this paper, we will discuss the role of several agents on the simultaneous modulation of these two central longevity pathways. The aging of western societies makes prevention of age-related diseases a pressing priority.

Keywords: Age-related diseases, FoxO, HSF1, Longevity, Pathway, Therapy, proteotoxicity, beta-amyloid fibrils