Path 11: Dysbiosis & Extrinsic Factors

Rationale: Microbiome and environment: the external contributors to aging. Age-related changes in our commensal microbiome, circulatory environment, and hormones influence aging. Dysbiosis (altered gut microbiota with age) can increase gut permeability and inflammation. Young blood contains “youth factors” that can rejuvenate old tissues, while old blood has “pro-aging factors.” Endocrine changes alter the systemic milieu.

Prerequisites: Microbiology (gut flora metabolism), physiology, endocrinology.

Dependencies: Overlaps with Path 10 (inflammation) – a leaky gut drives systemic inflammation. Interacts with Path 9 (stem cells) since the systemic environment affects stem cell behavior.

Signs of Progress: Clinical trials showing gut microbiome modification in older adults leads to health improvements. Identification of key metabolites from young microbiomes producing anti-aging effects. Plasma exchange or neutralizing specific pro-aging factors yielding rejuvenation. “Blood factor” therapies reaching clinical trials.

BC11.1: The Aging Microbiome

Scope: Gut microbiota composition changes with age: less diversity, less beneficial anaerobes, more opportunistic bacteria. Altered metabolite production.

• O’Toole, P.W. & Jeffery, I.B. “Gut microbiome and aging.” Science, 2015. – Concise overview of known changes with key points.
• Biagi, E. et al. “Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians.” PLoS ONE, 2010. – Real data linking microbiome to inflammation in aging.
• Xu, C. et al. “The global landscape of aging microbiomes.” Nat. Commun., 2022. – Large dataset analysis of how microbiomes vary with age across populations.

BC11.2: Endocrine and Neuroendocrine Aging

Scope: GH/IGF-1 decline, sex hormones (menopause/andropause), thyroid, adrenal cortisol, melatonin.

• Harman, S.M. et al. “Longitudinal effects of aging on serum testosterone levels in healthy men.” J. Clin. Endocrinol. Metab., 2001. – Data on testosterone decline.
• Vitale, C. et al. “Gender differences in the cardiovascular effect of sex hormones.” Nat. Rev. Cardiol., 2009. – Estrogen/progesterone vs testosterone effects on heart.
• Pollak, M. “Insulin and insulin-like growth factor signalling in neoplasia.” Nat. Rev. Cancer, 2008. – Why lower GH/IGF in aging might be adaptive against cancer.

BC11.3: Systemic “Milieu” Rejuvenation

Scope: Plasma dilution, young plasma/CSF infusions, drugs mimicking youth, JAK/STAT inhibition.

• Mehdipour, M. et al. “Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin.” Aging (Albany NY), 2020. – Plasma dilution: removing old factors rather than adding young ones.
• Castellano, J.M. et al. “Human umbilical cord plasma proteins revitalize hippocampal function in aged mice.” Nature, 2017. – Factors in human cord blood improving cognition in mice.
• Baumann, K. “Ageing: Diluting blood to rejuvenate the body.” Nat. Rev. Mol. Cell Biol., 2020. – News & views piece summarizing Conboy plasma dilution study.

BC11.4: Cross-Linking and Extracellular Aging

Scope: Glycation leading to AGEs, cross-links between collagen/elastin, tissue stiffening. Cross-link breakers (alagebrium).

• Page, K.M. et al. “Assessing the role of glycation in human brain aging.” Neurobiol. Aging, 2018. – AGEs in the brain in aging and Alzheimer’s.
• Sims, T.J. et al. “Ageing and cross-linking of skin collagen.” Biochem. J., 1991. – Classic measurement study showing collagen crosslinking increases with age.
• Vasan, S. et al. “An agent cleaving glucose-derived protein crosslinks.” Nature, 1996. – Initial report of ALT-711 breaking crosslinks.

Bibliography (Path 11)

• O’Toole, Paul W. & Ian B. Jeffery. “Microbiome–Health Interactions in Older People.” Cell. Mol. Life Sci. 75(1): 119–128, 2018. (Gut microbiota changes in elderly)
• Thevaranjan, N. et al. “Age-Associated Microbial Dysbiosis Promotes Intestinal Permeability.” Cell Host Microbe 21(4): 455–466, 2017. (Aging gut microbiome to leaky gut and inflammation)
• Cox, Laura S. & Richard Faragher. “From Old Bodies to Healthier Brains.” Rejuvenation Res. 16(6): 516–524, 2013. (Pharmacological rejuvenation of systemic environment)
• Baar, Matthew P. et al. “Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis.” Cell 169(1): 132–147, 2017. (Senolytic ABT-263 alleviated chemotherapy-induced bone marrow aging)
• Campisi, Judith et al. “From Discoveries in Ageing Research to Therapeutics for Healthy Ageing.” Nature 571(7764): 183–192, 2019. (Broad roadmap including young plasma trials, metformin, senolytics)