Regulation of reproduction and longevity by nutrient-sensing pathways

Abstract

Nutrients are necessary for life, as they are a crucial requirement for biological processes including reproduction, somatic growth, and tissue maintenance. Therefore, signaling systems involved in detecting and interpreting nutrient or energy levels-most notably, the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway, mechanistic target of rapamycin (mTOR), and adenosine monophosphate-activated protein kinase (AMPK)-play important roles in regulating physiological decisions to reproduce, grow, and age. In this review, we discuss the connections between reproductive senescence and somatic aging and give an overview of the involvement of nutrient-sensing pathways in controlling both reproductive function and lifespan. Although the molecular mechanisms that affect these processes can be influenced by distinct tissue-, temporal-, and pathway-specific signaling events, the progression of reproductive aging and somatic aging is systemically coordinated by integrated nutrient-sensing signaling pathways regulating somatic tissue maintenance in conjunction with reproductive capacity.

Figure 1.

IIS and its effects on reproduction and longevity. Many IIS components have been shown to affect reproductive function (green asterisks) and/or lifespan (orange asterisks) in C. elegans, D. melanogaster, and/or mice; these signaling components are indicated by asterisks in this simplified IIS schematic. ILP ligands bind to a transmembrane IIS tyrosine kinase receptor (DAF-2 in C. elegans), which autophosphorylates and then recruits and activates key substrates, either directly or through receptor substrate intermediates. In the PI3K/Akt branch of IIS (left), activated PI3K converts PI(4,5)P₂ into second messenger PI(3,4,5)P₃; PI(3,4,5)P₃ levels are negatively regulated by phospholipid phosphatases such as the PI3-phosphatase PTEN. PI(3,4,5)P₃ stimulates recruitment and activation of 3-phosphoinositide–dependent protein kinase-1 (PDPK1) and its substrate, Akt/protein kinase B. Once activated through phosphorylation, Akt phosphorylates many cellular substrates not depicted in this image, including the Rab-GTPase–activating protein AS160, glycogen synthase kinase-3, and TSC1/TSC2. One key target of Akt is the FoxO transcription factor (DAF-16 in C. elegans); phosphorylation by Akt results in its exclusion from the nucleus and prevention of its transcriptional activity. In the Ras/MAPK branch of IIS (right), binding of the adapter protein Grb2 and the guanine nucleotide exchange protein Son of sevenless (SOS) to the activated IIS receptor, either directly or via a docking protein, allows SOS to catalyze a transformation of inactive GDP-bound Ras to active GTP-bound Ras. The activated small GTPase Ras stimulates activation of the serine/threonine kinase Raf, which leads to stepwise phosphorylation and activation of MEK1/MEK2 and then ERK1/ERK2. Activated ERK1/2 phosphorylates many cellular and nuclear substrates not depicted in this image, including RSK and the transcription factor ELK1. Blue arrows indicate phosphorylation (kinase activity); red arrows indicate dephosphorylation (phosphatase activity).

Figure 2.

mTORC1 signaling and its effects on reproduction and longevity. Many mTOR signaling components have been shown to affect reproductive function (green asterisks) and/or lifespan (orange asterisks) in C. elegans, D. melanogaster, and/or mice; these signaling components are indicated by asterisks in this simplified mTOR schematic. The serine/threonine kinase mTOR is the catalytic subunit of two distinct complexes, mTORC1 (which includes the constituent protein Raptor, among others) and mTORC2 (which includes the constituent protein Rictor, among others). The kinase activity of mTORC1 is strongly stimulated by the GTP-bound form of Rheb (Ras homologue enriched in brain); mTORC1 is thereby negatively regulated by TSC1/TSC2 complex, which converts Rheb to its inactive GDP-bound state. mTORC1 activity can be directly regulated (i.e., by AMPK or Akt phosphorylating constituent proteins of the complex or by rapamycin acutely inhibiting mTORC1 activity), but upstream signals also indirectly control mTORC1 activity through the TSC1/2 repressor. For instance, effector kinases of the PI3K/Akt and Ras/MAPK branches of IIS (Akt or ERK1/2 and RSK, respectively) inactivate the TSC1/2 complex. In contrast, phosphorylation by AMPK increases GTPase-activating protein activity of TSC2 toward Rheb, leading to inhibition of mTORC1 activity. Other upstream regulators (not depicted) also control mTORC1 activity. mTORC1 phosphorylates many substrates, including S6K.

Figure 3.

Regulation of energy homeostasis, reproductive processes, and somatic growth or maintenance by signaling pathways that perceive and respond to nutrient availability. (A) Nutrient abundance leads to increased insulin/IGF-1 and mTORC1 signaling, which collectively promote cellular processes that support energy storage or expenditure, increased reproduction, and growth. (B) Nutrient depletion leads to increased AMPK signaling and transcriptional activity of FoxO transcription factors, which promote protective cellular processes that support energy production or conservation, maintenance of reproductive function rather than progeny production, and lifespan extension. This simplified model does not account for macronutrient-specific responses or tissue-specific nutrient detection, and it does not distinguish between different tissues when summarizing downstream signaling effects. Black arrows indicate increased stimulation of a signaling pathway in response to the environmental conditions, and gray dotted arrows indicate little or no stimulation of a signaling pathway under the environmental conditions. Large text or arrows indicate relatively high levels of signaling compared with small text or arrows; blue indicates up-regulation or promotion, and red indicates down-regulation or suppression.