Path 5: Loss of Proteostasis

Rationale: The garbage catastrophe: proteins misfolding and aggregating. This path tackles aging as a failure of protein quality control. Youthful cells keep their proteins properly folded and degrade damaged proteins via the proteasome and autophagy. With age, these systems decline, leading to misfolded or cross-linked proteins accumulating (amyloid plaques, tau tangles, alpha-synuclein, lipofuscin). Boost the proteostasis network – chaperones, proteasomes, autophagy, breaking cross-links – and we might delay aging.

Prerequisites: Biochemistry (protein structure and folding), cell biology (ubiquitin-proteasome system, autophagy-lysosome pathway).

Dependencies: Overlaps Path 7 (nutrient sensing) because dietary and metabolic interventions often affect proteostasis. Links to Path 6 (mitochondrial) via mitophagy, and to Path 10 (inflammation) via protein aggregates triggering inflammatory responses.

Signs of Progress: Drugs or genetic tweaks that markedly improve proteostasis in old animals and extend their lifespan. Successful clearance of aggregates via immunotherapy. Breaking AGE cross-links in tissues restoring elasticity.

BC5.1: Protein Homeostasis Systems

Scope: Review how cells maintain protein quality. Cover molecular chaperones, ubiquitin-proteasome system, and autophagy-lysosome system.

• Hipp, M.S., Park, S.H. & Hartl, F.U. “Proteostasis impairment in aging and disease.” Science, 2014. – Lucid review by Hartl explaining the proteostasis network and how it fails in aging.
• Klionsky, D.J. et al. “Autophagy in major human diseases.” EMBO J., 2021. – Sections on autophagy’s role in aging and longevity.
• Riera, C.E. & Dillin, A. “Can aging be ‘defined’ as an ultimately failing proteostasis?” Protein Homeostasis in Health & Disease, 2015. – Ties chaperones, proteasome, and autophagy into a unified idea.

BC5.2: Age-Related Protein Aggregation

Scope: Study examples of “garbage” that accumulates: lipofuscin, extracellular aggregates (amyloid plaques, senile cardiac amyloid), intracellular aggregates (tau, Lewy bodies), cross-linked ECM proteins.

• Koga, H., Kaushik, S. & Cuervo, A.M. “Protein homeostasis and aging: The importance of exquisite quality control.” Ageing Res. Rev., 2011. – How various protein aggregates form when quality control fails.
• Taylor, R.C. & Dillin, A. “XBP-1 is a cell-nonautonomous regulator of stress resistance and longevity.” Cell, 2013. – Activating UPR in neurons led to whole-organism lifespan extension in C. elegans.
• Morimoto, Richard I. “The heat shock response and proteostasis in aging and disease.” Cold Spring Harb Perspect Biol., 2019. – How the heat shock response weakens with age.

BC5.3: Autophagy and Longevity

Scope: Focus on autophagy’s role in extending lifespan. CR, mTOR inhibition, spermidine all induce autophagy.

• Madeo, F. et al. “Essential role for autophagy in life span extension.” J. Clin. Invest., 2015. – Clear review making the case that autophagy is required for most life-extension.
• Mizushima, N. & Levine, B. “Autophagy in human diseases.” N Engl J Med, 2020. – Aging is associated with autophagy decline; boosting autophagy might combat age-related diseases.
• Bento, C.F. et al. “The role of autophagy in aging and age-associated diseases.” Brit. J. Pharm., 2016. – Broad review linking autophagy with various age-related issues.

BC5.4: Therapeutics Targeting Proteostasis

Scope: Pharmacological chaperones, proteasome activators, autophagy inducers, cross-link breakers, immunotherapy for aggregates.

• Sampaio-Marques, B. et al. “Spermidine improves healthy lifespan by enhancing autophagy.” Nature, 2016. – Spermidine extends lifespan by inducing autophagy.
• Kirkland, J.L. & Tchkonia, T. “Senolytic drugs: from discovery to translation.” J Intern Med, 2020. – Clearing senescent cells can indirectly improve tissue proteostasis.
• Zhou, Q. et al. “Boosting proteasome activity as a strategy to reduce proteotoxicity.” Biochem. Soc. Trans., 2016. – Attempts to enhance the proteasome.

Bibliography (Path 5)

• Taylor, J. Paul et al. “Decoding ALS: From Genes to Mechanism.” Nature 539(7628): 197–206, 2016. (Accessible explanation of proteostasis failure in disease, parallels aging)
• Morimoto, Richard I. & David L. Selkoe. “The Collapse of Proteostasis in Aging and Disease.” Cold Spring Harb. Perspect. Biol. 2(11): a00444, 2010. (Clear review of chaperone/proteasome/autophagy decline with age)
• Hipp, Martina S. et al. “Proteostasis Impairment in Aging and Neurodegeneration.” Science 324(5929): 364–366, 2014. (Aging cells cannot maintain proteome quality)
• López-Otín, Carlos et al. “The Proteostasis Network and Its Role in Aging.” Chapter in Functional Genomics of Aging, Springer, 2016. (Components and interventions)
• Koga, Hiroshi et al. “Aging and Longevity in the Simplest Animal.” Invert. Reprod. Dev. 59(sup1): 39–44, 2015. (Hydra’s perpetual proteostasis maintenance and negligible senescence)