Nutrient-Response Mechanisms in Longevity

Many of the interventions shown in animal studies to slow aging involve changes in the mechanisms that respond to nutrient intake. In effect mimicking some fraction of the natural response to a reduced calorie intake. Cells become more frugal, engage in more repair and recycling. Over the long term this extends life span, though to a far greater degree in short-lived species than in long-lived species such as our own. These mechanisms occur in near all species, and have ancient origins. Improved survival in the face of seasonal famine was an early winner in the evolutionary arms race. But a season is a large fraction of a mouse life span, and a small fraction of a human life span, so only the mouse has evolved to exhibit a sizable gain in life span when food is scarce.

The rate of aging and lifespan regulation depend on genetic and non-genetic or environmental factors. A significant amount of data has now established that the environment has a profound effect on lifespan regulation, with diet and stress being predominant factors determining survival, at the cellular, tissue, and organismal levels. Cells perceive nutrients, i.e., amino acids and sugars, through nutrient-responsive pathways that are hard-wired to basic metabolic processes, such as gene transcription, protein translation, proteostasis, and protein degradation rates, mitochondrial function, such as detoxification and respiration, as well as autophagy.

In this review, we provide a framework of knowledge about the role of nutrient-responsive pathways in lifespan and healthspan regulation, such as the Insulin Growth Factor (IGF) and mechanistic Target of Rapamycin (mTOR), and an update on the advancements in this scientific field. We briefly refer to fundamental principles of these pathways. In summary, activation of the related signaling controlled by IGF and mTOR, while beneficial early in life, supporting growth and development, seems detrimental in lifespan and healthspan. While the fundamental molecular players around these pathways - although not fully characterized - are sketched on a satisfactory level within simpler organisms, such as yeasts, D. melanogaster, and C. elegans, additional studies are needed to understand functional links on a genome-wide scale. Moreover, single or combinatorial drug treatments that target specific nutrient-responsive and other signaling pathways that affect growth, have been utilized to test effects on lifespan, as well as in healthspan, such as, amelioration of pathological states that might phenocopy age-related diseases or syndromes.

Nevertheless, genetics, as well as epigenetics, of human aging and the role of diet on human lifespan regulation are still being worked out. The field is utilizing stem cell technologies, patient samples, and organoids to bridge this gap and has found itself mature enough to proceed to large studies and clinical trials using mammalian species close to humans, such as dogs. However, cross-species comparisons reveal differential tempos, not only in differentiation programs but also within fundamental processes, such as proteostasis and protein half-life patterns, that can affect aging processes and lifespan and healthspan. These studies show that the precise, quantitative outcomes in model organisms might differ from conditions in the human body or even in human cohorts. Therefore, although the contribution of model organisms in biogerontology studies is significant in understanding underlying molecular mechanisms, interdisciplinary studies combining genetics, biomarker analyses, diet and drug surveys, and interventions in human populations are now needed within the field.


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