Decades of research have demonstrated that a balanced diet is elemental for human health. Dietary imbalance affects all socioeconomic levels and cultures, with health conditions such as diabetes, hypertension, and heart disease associated with obesity, and osteoporosis, anemia, developmental defects, and increased risk of infection linked to nutritional deficits. Despite the critical importance of nutrition in health, our understanding of how individual nutrients effect the cellular changes associated with aberrant states is at its infancy. The underlying hypothesis for our work is that components of a balanced diet coordinately influence signal transduction pathways in target cells, resulting in harmonious conditions that promote health.
In general, diet-associated health conditions increase with age. Recent work demonstrating that dietary alteration can reduce symptoms of aging is encouraging, suggesting that defining optimal diets for individuals based on their genetics and physiology may improve health. Dietary restriction (DR), defined as the reduction of total calories without malnutrition, can have long-lasting positive effects. Reduced intake of nutrients such as sugar and cholesterol improve metabolism, diminishing stress, as well as risk factors for diabetes and atherosclerosis. In addition, DR affects adult stem cells, which are the key to healthy tissue maintenance and repair over the lifetime of an organism. Stem cells also age. Over time, the ability of a stem cell to self-renew and maintain a population of multipotent cells diminishes. Production of functional daughter cells also decays over time, eventually limiting the ability of tissues to function adequately. During aging, cellular characteristics including genomic instability, changes in gene expression and epigenetic modifications, energy production, recycling and turnover of damaged and short-lived proteins, altered cell-cell communication, and loss of nutrient sensing challenge stem cells. Together, these cellular conditions promote senescence, a condition whereby stem cells are present in the tissue, but no longer function. Like the organism in general, dietary restriction reduces the cellular conditions that drive stem cell aging, resulting in improved stem cell function and tissue health.
The concept of using DR to promote healthy aging is intriguing, as it is a nonspecific approach that generally improves health without a clear understanding of its impact at the cellular level. The power of DR presents an ideal opportunity to investigate the cellular and molecular mechanisms responsible for the observed health improvements. Our work focuses on 2 major diet-regulated signaling pathways that are critically important in age-associated health conditions. INS (insulin) and IGF (insulin like growth factor) signaling (IIS) are primary effectors of DR. Reduced IIS is associated with improved age-associated symptoms, and extends longevity in evolutionarily divergent organisms. A paradox arises, however, regarding the impact of IIS on stem cells. Some tissue stem cells exhibit reduced hallmarks of aging in both dietary restriction and reduced IIS conditions, consistent with IIS mediating the stem cell response to dietary restriction. Conversely, stem cells in the reproductive systems of worms, flies, and mice depend on IIS for their maintenance and long-term function, while beneficial effects of dietary restriction are still observed. Thus, additional nutrient-regulated pathways must modulate IIS to meet the tissue-specific stem cell needs.
Our previous work implicated cholesterol as a nutrient modulator of feeding in epithelial follicle stem cells (FSCs) in the Drosophila ovary. In the ovary, cholesterol triggers release of the hh (hedgehog) ligand from producing cells, driving HH activation within FSCs. The resulting boost in FSC proliferative rate was expected to promote a competitive advantage, which would allow these cells to vie for niche occupancy after each cell division. Instead, FSCs with high hh signaling were driven out of the niche, undergoing differentiation instead [Citation1]. Reminiscent of the IIS paradox, these results suggest that HH is simultaneously driving the proliferation that maintains a long-lived, youthful state, and responses that promote rapid FSC aging. A genetic screen for modifiers of fertility defects caused by constitutive hh activation revealed core autophagy regulators as robust suppressors. Strikingly, all known autophagy regulators affected the hh response, with reduced function of autophagy-promoting kinases including Pka, Lkb1, and AMPK suppressing hh-mediated autophagy induction. Conversely, activation of the negative regulator Tor suppresses hh-induced autophagy. Autophagy induction is prevalent in FSCs in young flies with high levels of hh signaling. Autophagy also is induced in middle age, when fertility begins to diminish. Autophagy profoundly affects FSCs and fertility, as autophagy induction in young flies reduces FSC lifespan, and genetic ablation of autophagy ameliorates the early sterility observed in high hh signaling conditions. Thus, autophagy is both a beacon and a sentry for FSC aging, acting to signal decreased FSC fitness and arresting reproduction under suboptimal conditions.
Surprisingly, autophagy induction in FSCs depends on ptc/patched, a well-studied hh pathway component. Usually, ptc functions to suppress the activity of smo in the absence of hh ligand, promoting transcriptional activation through relief of smo inhibition in its presence. In contrast to this nearly ubiquitous role, ptc activates autophagy in an hh-dependent, but smo- and transcription-independent manner in FSCs. ptc functional domains distinct from those required to inhibit smo promote autophagy via Pka, Lkb1, AMPK, and Atg1/ULK1. This novel function suggests a need to revisit potential alternative roles for hh during development. hh may induce autophagy in tissues or organisms that lack smo, or modify cells independently of transcriptional programs.
hh induction of autophagy and proliferation simultaneously presents a problem for FSCs. As activation of both responses drives FSC differentiation, autophagy must be suppressed for FSCs to be maintained. Here, IIS comes to the rescue. IIS activation prevents hh-induced autophagy, extending stem cell lifespan and fertility. Reduced IIS in young FSCs permits hh-induced autophagy, demonstrating its critical role in autophagy suppression. Most likely, dietary restriction maintains the hh-IIS signaling balance, as nutrients that stimulate both pathways would be reduced coordinately. This has interesting implications for aging and health conditions associated with IIS imbalance, such as polycystic ovary syndrome (PCOS), and hypertension and atherosclerosis associated with type II diabetes. Targeting this balance in malignancies such as pancreatic cancer, where insulin resistance and cholesterol are negatively correlated with outcomes, and autophagy inhibition shows promise, may provide new therapeutic avenues for prevention and treatment.
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- Singh T, Lee EH, Hartman TR, et al. Hedgehog and Insulin balance proliferation and autophagy to maintain follicle stem cell fitness in the Drosophila ovary. Dev Cell. 2018;46:720–734.