April 2023 Longevity Review

Epigenetic partial reprogramming remains the hottest topic in longevity research and this month sees an important advancement with the first claimed results in a nonhuman primate. There are also indications that exercise and an anti-hypertensive can slow down epigenetic ageing, as well as vitamin D reducing all cause mortality, lymphocytes from young animals preserving hearing and a telomerase activator helping those who have had a heart attack.

In the Supplemental section, you’ll find a couple of in depth reviews looking at the use of gene therapy and stem cells to combat ageing, the benefits of collagen, and a disappointing study on the bioavailability of spermidine. In Opinions there are also three articles on that perennial longevity argument: is ageing programmed or just the result of lifetime damage. And of course much more!

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CLA News

Fingers crossed, but hopefully I will have some big news to share with you next month regarding the final set-up of the CLA. I don’t want to jinx it, but we’re almost at the finish line and can then get on with fulfilling our mission and making a difference in Canada.

In the meantime, I want to extend a warm welcome to Martina, our newest active volunteer!

April 2023 Round-Up:

An important step in translating epigenetic reprogramming to humans, this press release marks the first time results have been seen in nonhuman primates. Building on from the groundbreaking 2020 study which restored vision in mice with glaucoma, this study dealt with another optic disease called NAION, which is incurable. However, the introduction of three Yamanaka factors, OSK, restored visual function and increased nerve axon survival. It will still be a while, but as David Sinclair tweeted: “Next step humans”.
Life Biosciences Presents Groundbreaking Data at ARVO Demonstrating Restoration of Visual Function in Nonhuman Primates Full Text (Press Release)

While waiting for epigenetic rejuvenation, this next study shows that physical activity can slow down epigenetic ageing, with the greatest reduction in GrimAge at 11K steps per day or 1.5 daily hours of moderate to vigorous physical activity. In addition, the second study showed that HIIT for one month reduced transcriptomic age by 3.5 years as well as improving depression, sleep and body composition.
*Physical activity is associated with slower epigenetic ageing—Findings from the Rhineland study Full Text
*High-Intensity interval training reduces transcriptomic age: A randomized controlled trial Full Text

Sticking with epigenetic ageing, this observational study, looking at medication usage over 13 years and epigenetic ageing, found that calcium channel blockers reduced several different age clocks (by 0.57 to 1.74 years) and improved functional age and frailty indexes.
*Certain Medications Appear to Improve Aging Biomarkers Full Text

This systematic review of 80 studies showed that users of vitamin D had a small (5%) reduction in all cause mortality. Considering how cheap vitamin D is, it’s probably worth taking, though what the most effective dose is was not looked at in this study.
*Vitamin D Supplementation and Its Impact on Mortality and Cardiovascular Outcomes: Systematic Review and Meta-Analysis of 80 Randomized Clinical Trials Full Text

In this study, lymphocytes (a type of immune cell) from young mice were given to older ones and were found to prevent age related hearing loss and oxidative stress, probably through the rejuvenation of the immune system.
Inoculation of lymphocytes from young mice prevents progression of age-related hearing loss in a senescence-associated mouse model Full Text

And finally, this 12 month study of telomerase activator TA-65 in heart attack patients showed that it increased total lymphocytes, improving immune function, while reducing CRP (a marker of inflammation) and adverse events. Unfortunately, TA-65 is a pricey supplement and is outside my price range.
*Activation of telomerase by TA-65 enhances immunity and reduces inflammation post myocardial infarction Full Text

Supplemental Section

Lifestyle
*Nutrition and exercise interventions to improve body composition for persons with overweight or obesity near retirement age: A systematic review and network meta-analysis of randomised controlled trials Full Text
*How can we modulate aging through nutrition and physical exercise? An epigenetic approach Full Text

Fasting/Dietary Restriction – certainly the cheapest & also one of the most effective anti-ageing interventions currently available. It comes in many flavours, but I fast for at least 12 hours every day.
Ketone bodies: A double-edged sword for mammalian life span Full Text
*Intermittent fasting modulates the intestinal microbiota and improves obesity and host energy metabolism Full Text
*Fasting diet reduces risk markers of type 2 diabetes Full Text
The hunger games as the key to happily ever after? Full Text

Diet – let food be thy medicine…
*Replacement of dietary saturated with unsaturated fatty acids is associated with beneficial effects on lipidome metabolites: a secondary analysis of a randomized trial Full Text
*Even or skewed dietary protein distribution is reflected in the whole-body protein net-balance in healthy older adults: A randomized controlled trial Full Text
*Low Carb Intake Linked to Insulin Resistance Full Text (March 2023)

Exercise – if you could bottle the benefits of exercise, it would be the biggest blockbuster drug of all time.
*How long have you exercised in your life? The effect of motor reserve and current physical activity on cognitive performance Full Text

Non-prescription Supplements (in alphabetical order)
NOTE - the supplements selected below are not exhaustive. They reflect what I thought were the most interesting ones back in 2019, with only a few updates since. I do individual searches for each and simply do not have time to do all others. Additionally, I’ve noticed how a lot of natural supplements affect the same genetic pathways, so I think that there is a lot of overlap and redundancy.

Astaxanthin – which is behind the pink colour of salmon & shrimp. Considered the most powerful carotenoid, it has anti-oxidative, anti-inflammatory, anti-cancer, neuro-protective and skin-protective qualities.
Astaxanthin suppresses oxidative stress and calcification in vertebral cartilage endplate via activating Nrf-2/HO-1 signaling pathway Full Text

Curcumin – the spice which gives curries their yellow colour. Anti-inflammatory and neuroprotective. Needs to be taken with black pepper (piperine) to improve bioavailability.
*Exploring the Contribution of Curcumin to Cancer Therapy: A Systematic Review of Randomized Controlled Trials Full Text
*An updated meta-analysis of effects of curcumin on metabolic dysfunction-associated fatty liver disease based on available evidence from Iran and Thailand Full Text

Fisetin
Fisetin Attenuates Paracetamol-Induced Hepatotoxicity by Regulating CYP2E1 Enzyme Full Text
Network pharmacology identifies fisetin as a treatment for osteoporosis that activates the Wnt/β-catenin signaling pathway in BMSCs Full Text

Melatonin – a natural hormone produced in the pineal gland, it helps us fall asleep every night, but it has many other functions, including as a mitochondrial antioxidant.
*The effect of melatonin on irritable bowel syndrome patients with and without sleep disorders: a randomized double-blinded placebo-controlled trial study Full Text
Co-administration of exercise training and melatonin on the function of diabetic heart tissue: a systematic review and meta-analysis of rodent models Full Text

Nicotinamide MonoNucleotide (NMN)
NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency Full Text (& NR)

Nicotinamide Riboside (NR)
*Oral supplementation of nicotinamide riboside alters intestinal microbial composition in rats and mice, but not humans Full Text
Preclinical characterization of pharmacological NAD+ boosting as a promising therapeutic approach in Rheumatoid Arthritis Full Text (& NAM)

Pterostilbene
Pterostilbene could alleviate diabetic cognitive impairment by suppressing TLR4/NF-кB pathway through microbiota-gut-brain axis

Resveratrol
*Resveratrol supplementation: a therapeutic potential for cardiac remodeling in hypertensive heart disease Full Text
*Effect of Resveratrol on Markers of Oxidative Stress and Sirtuin 1 in Elderly Adults with Type 2 Diabetes Full Text
Resveratrol for dry eye disease – Hope or Hype? Full Text

Spermidine
*High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study Full Text
Restoring polyamine levels by supplementation of spermidine modulates hepatic immune landscape in murine model of NASH Full Text
Spermidine as a promising anticancer agent: Recent advances and newer insights on its molecular mechanisms Full Text

Other available supplements (in alphabetical order)
*Allulose for the attenuation of postprandial blood glucose levels in healthy humans: A systematic review and meta-analysis Full Text
Berberine is a potential alternative for metformin with good regulatory effect on lipids in treating metabolic diseases Full Text
*Ginseng intake and Alzheimer disease-specific cognition in older adults according to apolipoprotein ε4 allele status Full Text
Activating mitochondrial SIRT3 in chondrocytes alleviates aging-induced fibrocartilage layer degeneration and promotes healing of degenerative rotator cuff injury Full Text (Honokiol)
Role of Hydroxytyrosol and Oleuropein in the Prevention of Aging and Related Disorders: Focus on Neurodegeneration, Skeletal Muscle Dysfunction and Gut Microbiota Full Text
Long-term dietary n3 fatty acid prevents aging-related cardiac diastolic and vascular dysfunction Full Text

Combinations of Supplements
*Role of δ-tocotrienol and resveratrol supplementation in the regulation of micro RNAs in patients with metabolic syndrome: A randomized controlled trial Full Text
Potential nutritional strategies to prevent and reverse sarcopenia in aging process: role of fish oil-derived ω-3 polyunsaturated fatty acids, wheat oligopeptide and their combined intervention Full Text
D-galactose-induced aging mouse model by regulating CXCL12/CXCR4 and gut microbiota Full Text
Single-pill combination in the management of chronic coronary syndromes: A strategy to improve treatment adherence and patient outcomes? Full Text

Prescription Supplements

Metformin
*Metformin: evidence from preclinical and clinical studies for potential novel applications in cardiovascular disease Full Text
Molecular mechanisms of action of metformin: latest advances and therapeutic implications Full Text
*Extended-release metformin improves cognitive impairment in frail older women with hypertension and diabetes: preliminary results from the LEOPARDESS Study Full Text

Rapamycin (sirolimus)
Rapamycin, the only drug that has been consistently demonstrated to increase mammalian longevity. An update Full Text
Rapamycin Rescues Age-Impaired Blood Flow in Mice Abstract
Cancer prevention with rapamycin Full Text

Miscellaneous Molecules & Prescription Drugs
*A Phase 1 study for safety and pharmacokinetics of BIO101 (20-hydroxyecdysone) in healthy young and older adults Full Text
The Geroprotective Drug Candidate CMS121 Alleviates Diabetes, Liver Inflammation, and Renal Damage in db/db Leptin Receptor Deficient Mice Full Text
The role of GDF11 during inflammation – An overview Full Text
Humanin and Its Pathophysiological Roles in Aging: A Systematic Review Full Text
*Pioglitazone reduces cardiovascular events and dementia but increases bone fracture in elderly patients with type 2 diabetes mellitus: a national cohort study Full Text
Unlocking the Full Potential of SGLT2 Inhibitors: Expanding Applications beyond Glycemic Control Full Text (March 2023)
Repurposing Approved Drugs for Sarcopenia Based on Transcriptomics Data in Humans Full Text

Other Areas of Interest (in alphabetical order)

Ageing Clocks & other biomarkers of ageing
How stress can increase your biological age and how to reverse it Full Text
*New research finds age of your brain and body can appear many years older (or younger) than your chronological age Full Text
*Clinical biomarker-based biological aging and risk of cancer in the UK Biobank Full Text

Blood Factors or other Heterochronic Transplantation
Characterizing expression changes in noncoding RNAs during aging and heterochronic parabiosis across mouse tissues Full Text

Epigenetics & Cellular Reprogramming
Transcriptomic reprogramming for neuronal age reversal Full Text
Multi-omic underpinnings of epigenetic aging and human longevity Full Text
Reprogramming Fibroblasts in Vivo for Heart Repair Full Text

Exosomes (small packets of information released by cells)
Neuromuscular electrical stimulation enhances the ability of serum extracellular vesicles to regenerate aged skeletal muscle after injury Full Text
Small Extracellular Vesicles’ miRNAs: Biomarkers and Therapeutics for Neurodegenerative Diseases Full Text
Osteoimmune Interactions and Therapeutic Potential of Macrophage-Derived Small Extracellular Vesicles in Bone-Related Diseases Full Text

Genetics including CRISPR
Gene Therapy Strategies Targeting Aging-Related Diseases Full Text
Genetic perturbation of mitochondrial function reveals functional role for specific mitonuclear genes, metabolites, and pathways that regulate lifespan Full Text
Engineering longevity—design of a synthetic gene oscillator to slow cellular aging

Lifespan Lengthening Interventions
AI-Predicted mTOR Inhibitor Reduces Cancer Cell Proliferation and Extends the Lifespan of C. elegans Full Text
CRISPR-activated expression of collagen col-120 increases lifespan and heat tolerance Full Text
Dauer larva-derived extracellular vesicles extend the life of Caenorhabditis elegans Full Text

Microbiome
*Youth-associated signatures in the gut microbiome of centenarians Abstract
Forging the microbiome to help us live long and prosper Full Text
Role of gut microbiota in the modulation of the health effects of advanced glycation end‑products Full Text
Young bugs rejuvenate old blood Full Text

Observational Studies
*Life Course Engagement in Enriching Activities: When and How Does It Matter for Cognitive Aging? Full Text
*The impact of long-term conditions on the progression of frailty Full Text
*Trends in elevated waist-to-height ratio and waist circumference in U.S. adults and their associations with cardiometabolic diseases and cancer, 1999–2018 Full Text

Opinion/Editorials/Theory
Programmed versus non-programmed evolution of aging. What is the evidence? Full Text
Programmed ageing: decline of stem cell renewal, immunosenescence, and Alzheimer's disease Full Text
How does the body know how old it is? Full Text
The pursuit of health: A vitality based perspective Full Text
60 Years of Healthy Aging: On Definitions, Biomarkers, Scores and Challenges Full Text*

Other Ageing Biology
Age-Related Changes in RNA Transcription Speed Full Text
A hyper-quiescent chromatin state formed during aging is reversed by regeneration Full Text
Making young mice old in a matter of three weeks Full Text

Regenerative Medicine
Salivary gland regeneration: from salivary gland stem cells to three-dimensional bioprinting Full Text
Vascular cells improve functionality of human cardiac organoids full Text

Reproductive Health
Alpha-ketoglutarate supplementation ameliorates ovarian reserve and oocyte quality decline with aging in mice
Lovastatin, an Up-Regulator of Low-Density Lipoprotein Receptor, Enhances Follicular Development in Mouse Ovaries Full Text
Chito-oligosaccharides and macrophages have synergistic effects on improving ovarian stem cells function by regulating inflammatory factors Full Text

Reviews
How Does Chronobiology Contribute to the Development of Diseases in Later Life Full Text
A state-of-the-art review on the MicroRNAs roles in hematopoietic stem cell aging and longevity Full Text
Biological resilience and aging: Activation of stress response pathways contributes to lifespan extension Full Text
Responses to Many Anti-Aging Interventions Are Sexually Dimorphic Full Text

Senolytics/Senescent Cells
Senolytics rejuvenate the reparative activity of human cardiomyocytes and endothelial cells Full Text
Clearance of senescent cells reverts the cigarette smoke-induced lung senescence and airspace enlargement in p16-3MR mice Full Text
Impact of Senolytic Treatment on Gene Expression in Aged Lung Full Text

Skin & Beauty
*Optimized multiherbal combination and in vivo anti-skin aging potential: a randomized double blind placebo controlled study Full Text
*Collagen supplementation in skin and orthopedic diseases: A review of the literature Full Text (March 2023)
*A pilot study comparing the efficacy of autologous cultured fibroblast injections with hyaluronic acid fillers for treating nasolabial folds Full Text

Stem Cells
Netrin-1 Rescues Blood Stem Cells in Mice Full Text
*Recent clinical trials with stem cells to slow or reverse normal aging processes Full Text

Telomeres
Canonical and extra-telomeric functions of telomerase: Implications for healthy ageing conferred by endurance training Full Text
Exploring the Causal Relationship Between Telomere Biology and Alzheimer’s Disease Full Text

Odds & Sods
*Hyperbaric Oxygen Therapy Reduces Oxidative Stress and Inflammation, and Increases Growth Factors Favouring the Healing Process of Diabetic Wounds Full Text
Multi-tissue DNA methylation aging clocks for sea lions, walruses and seals Full Text

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***Disclaimer 1 – I am NOT a doctor or indeed a scientist. All the information pertained within is for information purposes only; use at your own risk. Please consult with a healthcare practitioner if you need medical advice.***

**Disclaimer 2 – In no way should supplements be a replacement for an unhealthy diet or lifestyle. A varied, plant dominant dietary pattern is the cornerstone for health. Try to eat the rainbow – the greater the variety, the greater the benefit. Even though I might take a supplement derived from a plant source, I still eat the plant in question. Also, make sure you move as much as possible – that is what we evolved to do.**

*Also bear in mind that most of the studies mentioned above are in rodents, not humans. Rodents, needless to say, do not always react the same way to drugs as humans do – witness the countless times cancer or another disease has been cured in rodents only to subsequently fail human trials. I have *starred any human trials.*
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