Path 7: Deregulated Nutrient Sensing (Metabolic Control)

Rationale: Master switches: insulin, mTOR, and the longevity diet. This path targets the metabolic signaling pathways that govern growth, reproduction, and resource use. Research discovered that dialing down growth signals often extends lifespan, while fasting or calorie restriction (CR) robustly extends lifespan in species from yeast to rodents. Key pathways: Insulin/IGF-1 signaling (IIS) – mutations can dramatically extend lifespan. mTOR – inhibiting with rapamycin extends lifespan. AMPK – energy sensor activating maintenance pathways. Sirtuins – NAD¹-dependent deacetylases linked to fasting and stress resistance.

Prerequisites: Biochemistry (metabolism), cell signaling, endocrinology.

Dependencies: Strong interplay with Path 5 (proteostasis) and Path 6 (mitochondria) because nutrient signals modulate autophagy and ROS production. Path 1 (evolutionary) provides context.

Signs of Progress: Next-generation mTOR modulators or safer CR mimetic drugs. Human trials (metformin in aging, rapalogs, NAD+ boosters) showing clear slowdown in multi-system aging markers. Achieving CR benefits without actual dieting via precise metabolic reprogramming.

BC7.1: Insulin/IGF-1 Signaling and Longevity

Scope: The first long-lived mutants: daf-2 in C. elegans. IIS pathway conserved: Ames dwarf and Snell dwarf mice with low GH/IGF live ~50% longer. FOXO upregulates stress response genes.

• Kenyon, Cynthia. “The first long-lived mutants: discovery of the insulin/IGF-1 pathway for aging.” Phil. Trans. R. Soc. B, 2011. – Kenyon’s own recounting, very clear and personal.
• Taguchi, A. & White, M.F. “Insulin-like signaling, nutrient homeostasis, and life span.” Annu. Rev. Physiol., 2008. – Review detailing how insulin/IGF signaling affects aging.
• Longo, V.D. & Fabrizio, P. “Regulation of longevity and stress resistance by nutrient-responsive signaling pathways.” Cell. Mol. Life Sci., 2012. – Emphasizes evolutionary conserved nature of longevity control.

BC7.2: mTOR and Caloric Restriction

Scope: mTOR kinase, central nutrient sensor. Rapamycin’s lifespan extension. CR in rodents and primates.

• Laplante, M. & Sabatini, D.M. “mTOR signaling in growth control and disease.” Cell, 2012. – Foundational review on mTOR.
• Fontana, L., Partridge, L. & Longo, V.D. “Extending healthy life span—from yeast to humans.” Science, 2010. – Comparative review of CR and related pathways.
• Bitto, A. et al. “Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice.” eLife, 2016. – Short course of rapamycin in mid-life had lasting benefits.

BC7.3: AMPK, Sirtuins, and NAD+

Scope: AMPK (low energy sensor), Sirtuins (NAD¹-dependent deacetylases). Raising NAD+ via precursors.

• Canto, C. & Auwerx, J. “Targeting sirtuin 1 to improve metabolism: all you need is NAD+?” Pharmacol. Rev., 2012. – Explains sirtuin biology and NAD+ clearly.
• Lopez-Otin, C. et al. “NAD+ metabolism and the control of energy homeostasis.” Cell Metab., 2016. – NAD+/sirtuin axis, how NAD declines with age.
• Garcia, D. & Shaw, R.J. “AMPK: Mechanisms of Cellular Energy Sensing.” Mol. Cell, 2017. – AMPK activation might extend lifespan.

BC7.4: Hormesis and Adaptive Stress Responses

Scope: Mild stress triggers nutrient signaling changes that bolster defenses. Exercise, heat, fasting, plant polyphenols.

• Mattson, Mark P. “Hormesis defined.” Ageing Res. Rev., 2008. – Brief introduction by a leading researcher.
• Ristow, M. & Schmeisser, S. “Mitohormesis: Promoting Health and Lifespan by Increased Levels of ROS.” Dose-Response, 2014. – Low doses of toxins extending lifespan via stress defenses.
• Flatt, T. & Heyland, A. (eds.) Mechanisms of Life History Evolution, 2011 – Chapter on “Hormetic Stress and Longevity”. – Evolutionary perspective: organisms evolved stress responses to handle adversity.

Bibliography (Path 7)

• Kenyon, Cynthia. “The First Long-Lived Mutants.” Phil. Trans. R. Soc. B 366(1561): 9–16, 2011. (Discovery of insulin/IGF-1 pathway for aging in C. elegans)
• Fontana, Luigi et al. “Extending Healthy Life Span—from Yeast to Humans.” Science 328(5976): 321–326, 2010. (CR and genetic pathways across species)
• Johnson, Simon C. et al. “mTOR Is a Key Modulator of Ageing.” Nature 493(7432): 338–345, 2013. (mTOR’s role in aging and how rapamycin impacts health/lifespan)
• Barzilai, Nir et al. “Metformin as a Tool to Target Aging.” Cell Metab. 23(6): 1060–1065, 2016. (Rationale for TAME trial targeting aging with metformin)
• Martínez de Toda, Irene et al. “Life-Extending Treatments and Senescence of the Insulin/IGF-1 Signalling System.” Proc. Nutr. Soc. 76(3): 444–455, 2017. (CR, protein restriction, compounds affecting insulin/IGF system)