October 2023 Longevity Review

Hello and welcome again to this month’s longevity review. The big news this month is that exosomes (small packets of chemical information cells use to communicate with each other) from young pig plasma were able to cross the species barrier and rejuvenate certain biomarkers in old rats. In addition, a small molecule was found to help repair older tendon injuries, a post conception rejuvenation event was confirmed in humans with big implications, and it was shown that the very old (+85) are still able to gain muscle mass and strength.

In the supplemental section, you’ll find the unsurprising news that alcohol and vaping accelerate epigenetic ageing, NMN and spermidine for reproductive health, reviews of glycine and resveratrol, how vaccinations can reduce incidence of dementia, hyperbaric oxygen therapy to improve bone health, and how in the last century the health and lifespan of marine mammals in captivity have mirrored the advances seen in humans. Plus of course much more!

Canadian Longevity Association News

The CLA celebrated International Longevity Day on the 1st of October with a photo in front of the 3D Toronto sign in Nathan Philip’s Square in Toronto, followed by drinks and discussion at a nearby venue. We had a banner of our logo specially printed for the photos. This event kicked off regular monthly meetups in Toronto - details of future events can be found on our FB group, LinkedIn page and newly resurrected Meetup group. Come and join us if you are around!
The CLA also attended a fantastic conference in Hamilton called Next Great Big Ideas, where some potentially very useful contacts were made. We also expanded our outreach, with some interesting developments slated for the new year - watch this space!

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October 2023 Round-Up:

I was super excited to read this paper, which almost falls into the too good to be true category. I’ve been following this research from the beginning and one of the primary leads is a reader of this newsletter, so risk of bias alert! In a nutshell, using a youthful plasma fraction containing an abundance of exosomes (small packets of chemical information cells use to communicate with each other), they cut the epigenetic age of rats by more than half and various other biomarkers returned to youthful levels. Equally noteworthy, the plasma fraction came from young pigs! This suggests that this modality crosses the species barrier and thus could also potentially be used for us, removing any ethical concerns and availability issues. The group are next validating this in dogs, which if equally efficacious will lead to human trials.
Plasma from Young Pigs Halves Old Rats’ Epigenetic Age Full Text

Damaged tendons are a major source of disability, which increases with age as their regenerative capacity decreases. Using machine learning, researchers discovered a natural small molecule, POG, that could improve the regenerative capacity of old tendons by decreasing senescence and inflammation, and increasing autophagy via suppressing mTOR and NF-kb. This was achieved either systematically or by localised injection for torn tendon repair, and by utilising a biomaterial scaffold for complete tendon cuts in rats. Results were replicated using older human tendon cell samples. This is a promising avenue for people to maintain or recover their activity levels in older ages.
Prim-O-glucosylcimifugin ameliorates aging-impaired endogenous tendon regeneration by rejuvenating senescent tendon stem/progenitor cells Full Text

A very important, but underappreciated paper in my view, which has some quite profound implications. Building on work in mice, this paper potentially confirms in humans that there is a rejuvenation event following conception. We are all born much biologically younger than the spermatozoa and ovum we originated from - a newborn looks like a newborn, not aged like its parents! This paper indicates that this rejuvenation event occurs 14 to 21 days after fertilisation, and is the moment we start to age. So, if we’ve already been rejuvenated once in our lives, why can’t science eventually rejuvenate us again?
Intersection clock reveals a rejuvenation event during human embryogenesis Full Text

Finally, onto a study applicable in the here and now. Loss of muscle mass not only leads to frailty, but is also associated with mortality. However, there is a common fear that people become too old to gain benefit from resistance exercise. This study should dispel that, as it showed that +85 year olds gained just as much muscle mass and strength as those 65-75, with both groups increasing muscle mass by around 10% and strength by 46% & 38% respectively over 12 weeks of 3x per week whole body progressive resistance training at 60%-80% 1 repetition maximum.
*Muscle Mass and Strength Gains Following Resistance Exercise Training in Older Adults 65–75 Years and Older Adults Above 85 Years Full Text

Supplemental Section

Lifestyle
*Association between a mediterranean lifestyle and Type 2 diabetes incidence: a prospective UK biobank study Full Text
*Association of a healthy lifestyle with mortality in older people Full Text
*Healthy lifestyle in late-life, longevity genes, and life expectancy among older adults: a 20-year, population-based, prospective cohort study 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.
*Calorie restriction modulates the transcription of genes related to stress response and longevity in human muscle: The CALERIE study Full Text
*Diet composition, adherence to calorie restriction, and cardiometabolic disease risk modification Full Text
*Effect of Time-Restricted Eating on Weight Loss in Adults With Type 2 Diabetes Full Text

Diet – let food be thy medicine…
*Diet strategies for promoting healthy aging and longevity: An epidemiological perspective Full Text
*Relationship between Composite Dietary Antioxidant Index and Aging Full Text
*The effects of olive oil consumption on cognitive performance: a systematic review Full Text

Exercise – if you could bottle the benefits of exercise, it would be the biggest blockbuster drug of all time.
*Dose–response effects of resistance training on physical function in frail older Chinese adults: A randomized controlled trial Full Text
*Effect of resistance training volume on body adiposity, metabolic risk, and inflammation in postmenopausal and older females: Systematic review and meta-analysis of randomized controlled trials 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 supplementation impact on insulin resistance, lipid profile, blood pressure, and oxidative stress in polycystic ovary syndrome patients: A triple-blind randomized clinical trial
Astaxanthin protects human ARPE-19 retinal pigment epithelium cells from blue light-induced phototoxicity by scavenging singlet oxygen
Astaxanthin promotes locomotor function recovery and attenuates tissue damage in rats following spinal cord injury: a systematic review and trial sequential analysis 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.
Evaluation of oxidative stress indicators as toxicity parameters after chronic exposure of Drosophila melanogaster to free curcumin and curcumin-loaded nanocapsules*
Targeting endothelial cells with golden spice curcumin: A promising therapy for cardiometabolic multimorbidity Full Text

Fisetin
PPARγ activation by fisetin mitigates vascular smooth muscle cell senescence via the mTORC2-FoxO3a-autophagy signaling pathway
DNA hypomethylation by fisetin preserves mitochondria functional genes and contributes to the protection of I/R rat heart

Melatonin
*Significant potential of melatonin therapy in Parkinson’s disease – a meta-analysis of randomized controlled trials Full Text
*The Effects of Melatonin Supplementation on Professional Football Player Performance: A Systematic Review Full Text
Non-Excitatory Amino Acids, Melatonin, and Free Radicals: Examining the Role in Stroke and Aging Full Text

Nicotinamide MonoNucleotide (NMN)
Improving lysosomal ferroptosis with NMN administration protects against heart failure Full Text
Inherited myogenic abilities in muscle precursor cells defined by the mitochondrial complex I-encoding protein Full Text
Hydroxyapatite-based nano-drug delivery system for nicotinamide mononucleotide (NMN): significantly enhancing NMN bioavailability and replenishing in vivo nicotinamide adenine dinucleotide (NAD+) levels

Nicotinamide Riboside (NR)
NAD+ Precursors: A Physiological Reboot? Full Text
*Long-Term Nicotinamide Riboside Use Improves Coordination and Eye Movements in Ataxia Telangiectasia Full Text

Pterostilbene
Changes in brown adipose tissue induced by resveratrol and its analogue pterostilbene in rats fed with a high-fat high-fructose diet Full Text

Resveratrol
*Effect of Resveratrol on Endothelial Function in Patients with CKD and Diabetes: A Randomized Controlled Trial
Resveratrol in Rheumatological Diseases: A Systematic Review Full Text
Resveratrol combats chronic diseases through enhancing mitochondrial quality Full Text

Spermidine
Changes in Whole Blood Polyamine Levels and Their Background in Age-Related Diseases and Healthy Longevity Full Text

Other available supplements (in alphabetical order)
*Vitamin C supplementation showed greater effects on systolic blood pressure in hypertensive and diabetic patients: an updated systematic review and meta-analysis of randomised clinical trials
Effects of the Acute and Chronic Administration of Cannabidiol on Cognition in Humans and Animals: A Systematic Review
Cannabidiol Modulates Emotional Function and Brain-Derived Neurotrophic Factor Expression in Middle-Aged Female Rats Exposed to Social Isolation Full Text
Protective Actions of Cannabidiol on Aging-Related Inflammation, Oxidative Stress and Apoptosis Alterations in Liver and Lung of Long Evans Rats Full Text
The Potential of Collagen Treatment for Comorbid Diseases Full Text
*Resistance Exercise and Creatine Supplementation on Fat Mass in Adults < 50 Years of Age: A Systematic Review and Meta-Analysis Full Text
Vitamin D Improves Cognitive Impairment and Alleviates Ferroptosis via the Nrf2 Signaling Pathway in Aging Mice Full Text
*Effects of DHA on cognitive dysfunction in aging and Alzheimer's disease: The mediating roles of ApoE Full Text
The effect of glycine administration on the characteristics of physiological systems in human adults: A systematic review Full Text
*Cognitive impact of multidomain intervention and omega 3 according to blood Aβ42/40 ratio: a subgroup analysis from the randomized MAPT trial Full Text
Unraveling the impact of Omega-3 polyunsaturated fatty acids on blood-brain barrier (BBB) integrity and glymphatic function Full Text
*Early Intervention in Cognitive Aging with Strawberry Supplementation Full Text
Pharmacological Effects of Urolithin A and Its Role in Muscle Health and Performance: Current Knowledge and Prospects Full Text
Overview of Ursolic Acid Potential for the Treatment of Metabolic Disorders, Autoimmune Diseases, and Cancers via Nuclear Receptor Pathways Full Text

Combinations of Supplements
The Combination of Citicoline and Nicotinamide Mononucleotide Induces Neurite Outgrowth and Mitigates Vascular Cognitive Impairment via SIRT1/CREB Pathway
Treatment of stroke in aged male and female rats with Vepoloxamer and tPA reduces neurovascular damage Full Text
Nicotinamide Riboside and Phycocyanin Oligopeptides Affect Stress Susceptibility in Chronic Corticosterone-Exposed Rats Full Text
Combination of curcumin and catalase protects against chondrocyte injury and knee osteoarthritis progression by suppressing oxidative stress Full Text

Prescription Supplements

Metformin
*Heterogeneous treatment effects of metformin on risk of dementia in patients with type 2 diabetes: A longitudinal observational study Full Text
*Metformin, age-related cognitive decline, and brain pathology
Old drug, new tricks: the utility of metformin in infection and vaccination responses to influenza and SARS-CoV-2 in older adults Full Text

Rapamycin (sirolimus)
Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease Full Text
Rapamycin Responds to Alzheimer’s Disease: A Potential Translational Therapy Full Text
Mechanistic target of rapamycin (mTOR): a potential new therapeutic target for rheumatoid arthritis Full Text

Miscellaneous Molecules & Prescription Drugs
Head-to-head comparison of BAM15, semaglutide, rosiglitazone, NEN, and calorie restriction on metabolic physiology in female db/db mice Full Text
A short peptide protects from age-onset proteotoxicity Full Text
The Effect of Liraglutide on Lung Cancer and Its Potential Protective Effect on High Glucose-Induced Lung Senescence and Oxidative Damage Full Text
Omentin-1 ameliorates the progress of osteoarthritis by promoting IL-4-dependent anti-inflammatory responses and M2 macrophage polarization Full Text
SGLT inhibitors for improving healthspan and lifespan Full Text

Other Areas of Interest (in alphabetical order)

Ageing Clocks & other biomarkers of ageing
*HOMA-IR is positively correlated with biological age and advanced aging in the US adult population Full Text
*Alcohol consumption and epigenetic age acceleration across human adulthood Full Text
*Accelerated epigenetic age, inflammation, and gene expression in lung: comparisons of smokers and vapers with non-smokers Full Text

Epigenetics & Cellular Reprogramming
*Blood DNA methylation signature of diet quality, and association with cardiometabolic traits Full Text

Exosomes (small packets of chemical information released by cells)
Nanotopographical Cues Tune the Therapeutic Potential of Extracellular Vesicles for the Treatment of Aged Skeletal Muscle Injuries Full Text
Extracellular Vesicles Derived from Osteogenic-Differentiated Human Bone Marrow-Derived Mesenchymal Cells Rescue Osteogenic Ability of Bone Marrow-Derived Mesenchymal Cells Impaired by Hypoxia Full Text

Genetics including CRISPR
Human Presenilin-1 delivered by AAV9 rescues impaired γ-secretase activity, memory deficits, and neurodegeneration in Psen mutant mice Full Text
Duplications of human longevity-associated genes across placental mammals Full Text
Genome-wide CRISPR activation screening in senescent cells reveals SOX5 as a driver and therapeutic target of rejuvenation

Lifespan Lengthening Interventions
Lactobacillus paracasei HII01 enhances lifespan and promotes neuroprotection in Caenorhabditis elegans Full Text
Thiadiazolidinone (TDZD) Analogs Inhibit Aggregation-Mediated Pathology in Diverse Neurodegeneration Models, and Extend C. elegans Life- and Healthspan Full Text
Hesperidin ameliorates Amyloid-β toxicity and enhances oxidative stress resistance and lifespan of Caenorhabditis elegans through acr-16 mediated activation of the autophagy pathway

Microbiome
*Effects of heat-killed Lactiplantibacillus plantarum TWK10 on exercise performance, fatigue, and muscle growth in healthy male adults Full Text
Bifidobacterium bifidum and Lactobacillus paracasei alleviate sarcopenia and cognitive impairment in aged mice by regulating gut microbiota-mediated AKT, NF-κB, and FOXO3a signaling pathways Full Text
Influence of gut microbiota on the development of most prevalent neurodegenerative dementias and the potential effect of probiotics in elderly: A scoping review Full Text

Observational Studies
*The association of herpes zoster and influenza vaccinations with the risk of developing dementia: a population-based cohort study within the UK Clinical Practice Research Datalink Full Text
*Association between daily alcohol consumption and serum alpha klotho levels among U.S. adults over 40 years old: a cross-sectional study Full Text
*Lower serum Klotho level and higher systemic immune-inflammation index: an inverse correlation Full Text
*Resting heart rate, cognitive function, and inflammation in older adults: a population-based study Full Text
*Serum Cholesterol and Impact of Age on Coronary Heart Disease Death in More Than 4 Million Veterans Full Text

Opinion/Editorials/Theory
Directional selection coupled with kin selection favors the establishment of senescence Full Text
Disease-modifying drugs for Alzheimer disease: implications for people in Canada Full Text

Other Ageing Biology
*AgingReG: a curated database of aging regulatory relationships in humans Full Text
HALL: a comprehensive database for human aging and longevity studies Full Text
A comprehensive AI-driven analysis of large-scale omic datasets reveals novel dual-purpose targets for the treatment of cancer and aging Full Text

Regenerative Medicine
Multi-species atlas resolves an axolotl limb development and regeneration paradox Full Text

Reproductive Health
β-nicotinamide mononucleotide rescues the quality of aged oocyte and improves subsequent embryo development in pigs Full Text
Spermidine May Improve Egg Health and Fertility Abstract
*Influence of Melatonin Treatment on Emotion, Sleep, and Life Quality in Perimenopausal Women: A Clinical Study Full Text

Reviews
The several ways to authentically cure Alzheimer’s dementia Full Text
A Narrative Review: The Effect and Importance of Carotenoids on Aging and Aging-Related Diseases Full Text
Mitochondria: A Potential Rejuvenation Tool against Aging Full Text

Senolytics/Senescent Cells
Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration following peripheral nerve injury Full Text
Senolytics prevent caveolar CaV3.2-RyR axis malfunction in old vascular smooth muscle Full Text
Potential Clinical Implications of Senotherapies for Cardiovascular Disease Full Text
*Biomarkers of cellular senescence and risk of death in humans Full Text

Skin & Beauty
*Low-molecular-weight collagen peptides supplement promotes a healthy skin: A randomized, double-blinded, placebo-controlled study Full Text
Skin ageing and topical rejuvenation strategies Full Text
*The Benefits of a Multimechanistic Antiaging Skin Technology Full Text

Stem Cells
How Nutrition Regulates Hematopoietic Stem Cell Features Full Text

Telomeres
*Differential Effects of Very-Low-Volume Exercise Modalities on Telomere Length, Inflammation, and Cardiometabolic Health in Obese Metabolic Syndrome Patients: A Subanalysis from Two Randomized Controlled Trials Full Text
Telomouse—a mouse model with human-length telomeres generated by a single amino acid change in RTEL1 Full Text
*The association of leukocyte telomere length with exceptional longevity among older women

Odds & Sods
*Effectiveness of photobiomodulation for people with age-related cognitive impairment: a systematic review and meta-analysis
Survival improvements of marine mammals in zoological institutions mirror historical advances in human longevity Full Text
Hyperbaric Oxygen Therapy Improves Bone Health in Rats Abstract
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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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