Enormous strides in understanding aging have come from the discovery that mutations in single genes can extend healthy life-span in laboratory model organisms such as the yeast Saccharomyces, the fruit fly Drosophila melanogaster, the nematode worm Caenorhabditis elegans and the mouse. IIS [insulin/IGF (insulin-like growth factor)-like signalling] stands out as an important, evolutionarily conserved pathway involved in the determination of lifespan.
The nicotinamide adenine dinucleotide (NAD)-activated protein deacetylase Sir2p/Sirt1 has been strongly implicated in the modulation of replicative lifespan and promotion of longevity. Part of Sirt1's capacity for lifespan extension in complex organisms may be attributed to its protective activity against neuronal degeneration. Manipulation of Sirt1's activity or levels by pharmacological and genetic means in several models of neurodegenerative diseases demonstrated its neuroprotective credentials.
Ageing is a progressive failure of defence and repair processes that produces physiological frailty (the loss of organ reserve with age), loss of homeostasis and eventual death. Over the past ten years exceptional progress has been made in understanding both why the ageing process happens and the mechanisms that are responsible for it. The study of natural mutants that accelerate some, but not all, of the features of the human ageing process has now progressed to a degree that drug trials are either taking place or can be envisaged.
TDP-43 is a multifunctional nucleic acid binding protein linked to several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia. To learn more about the normal biological and abnormal pathological role of this protein, we turned to Caenorhabditis elegans and its orthologue TDP-1. We report that TDP-1 functions in the Insulin/IGF pathway to regulate longevity and the oxidative stress response downstream from the forkhead transcription factor DAF-16/FOXO3a.
Although the underlying mechanisms of ageing are not understood, it is known that the longevity of the nematode Caenorhabditis elegans is modulated by an insulin/IGF-signalling pathway. The focus now is on how this pathway is regulated, how it controls nematode ageing, and how this relates to the ageing process in higher animals.
Reduced signaling of insulin-like peptides increases the life-span of nematodes, flies, and rodents. In the nematode and the fly, secondary hormones downstream of insulin-like signaling appear to regulate aging. In mammals, the order in which the hormones act is unresolved because insulin, insulin-like growth factor-1, growth hormone, and thyroid hormones are interdependent. In all species examined to date, endocrine manipulations can slow aging without concurrent costs in reproduction, but with inevitable increases in stress resistance.
Evolutionary theory predicts that the different life stages of organisms are coordinated to achieve maximal reproductive output. Moreover, aging can be seen as an evolutionary side effect of this selective process that applies to many living organisms. Hence, genetic, developmental, and physiological mechanisms resulting from this selection are expected to be conserved in diverse lineages. The insulin/insulin-like growth factor signaling (INS) pathway appears to be such a mechanism that regulates life span and reproduction in a variety of model organisms.