October 2022 Longevity Review

Posted by Chris Pollyanna , 10 November 2022 · 1,223 views

supplements rapamycin metformin fasting astaxanthin nad+ nmn resveratrol senolytics

Another month, another set of advances in the field of longevity including the publication of perhaps the most important paper of the year - showing synergy between senolytics and partial epigenetic reprogramming. More advances involved the use of extracellular vesicles, probiotics, and in the supplemental section astaxanthin showed benefits as well as SGLT-2 Inhibitors getting their own subsection this month.

Once again keeping this intro brief as shortly after my delayed return from Europe I moved for the first time in four years and am still awaiting an internet connection! Not sure the stress of moving was good for my longevity…

Canadian Longevity Association

Canadian Longevity Association YouTube Channel - where you can find video talk-throughs of these reviews.

We are always looking for more help or volunteers, regardless of your skill set or time availability. If you’d be interested in helping us, please fill out this Volunteer Registration Form.

For previous newsletters, you can find them in the Canadian Longevity Association Facebook group, and also my Patreon account, which includes bonus material for supporters if you want to buy me a coffee.

CLA News Chris’s n=1 Rapamycin Trial

Nothing major to report, apart from the fact I missed a dose in the middle of my move because I just plainly forgot. Still no noticeable effects both positive or negative.

Both my parents also started their trial and have now ramped up to their maintenance dose of 5mg.

October 2022 Round-Up:

OK, so this study already appeared in a previous round-up as a preprint, but I think it is significant enough to make another appearance with publication.

In this study, two completely different treatment modalities, senolytics & partial epigenetic reprogramming, were used to synergistically increase fruit flies’ median and maximum lifespan.

What makes this one of the most important papers published this year is that while you know I love combinations, for the most part that has involved two different drugs (eg Rapamycin & Acarbose) affecting different genetic pathways, whereas this study uses two completely different treatments (which also happen to be the two hottest areas in longevity research), targeting two different hallmarks of ageing. This is big.
Synergy Between Stem Cell Rejuvenation and Senolytics (April 2022)
Combining stem cell rejuvenation and senescence targeting to synergistically extend lifespan Full Text

Apart from the above, this study would have been the lead item this month as it showed that continuous partial epigenetic reprogramming of age accelerated mice increased their lifespan by 15%, and intriguingly a single course earlier in life achieved almost the same effect.
Cellular Reprogramming Extends Lifespan, Healthspan in Mice Full Text

Since we are on the subject of epigenetic reprogramming, I thought I would include this study which showed that centenarians naturally had a younger epigenetic age than their chronological one. Although this might seem obvious, it is nice to see this validation of the principle that a younger epigenetic age might lead to a longer life.
*Centenarians consistently present a younger epigenetic age than their chronological age with four epigenetic clocks based on a small number of CpG sites Full Text

Moving on from epigenetics, in this next study, extracellular vesicles (EVs) from young mice showed significant benefits in older animals - increasing fitness and hair regrowth, and decreasing senescence and epigenetic age. EVs are signalling molecules produced by stem cells and provide most of their benefit, however stem cells are difficult to deploy and EVs could be a simpler solution.
Extracellular Vesicles from Young Stem Cells Rejuvenate Mice Full Text

Finally, a simple probiotic powder of a particular strain of lactic acid bacteria over the course of twelve weeks improved memory for those whose memory was impaired. The effect seems to be through anti-inflammatory mechanisms. I wonder if we’ll see such bacteria appear in the yogurt sections of our supermarket shelves anytime soon?
*Effects of Lactiplantibacillus plantarum OLL2712 on Memory Function in Older Adults with Declining Memory: A Randomized Placebo-Controlled Trial Full Text

Supplemental Section

Lifestyle
*Less than five hours' sleep a night linked to higher risk of multiple diseases 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.
*Helping our heroes: Time-restricted eating improves health of firefighters Full Text
*Intermittent Fasting—Short- and Long-Term Quality of Life, Fatigue, and Safety in Healthy Volunteers: A Prospective, Clinical Trial Full Text
*Eating late increases hunger, decreases calories burned, and changes fat tissue Full Text
*Why late-night eating leads to weight gain, diabetes Abstract
*The impact of a self-selected time restricted eating intervention on eating patterns, sleep, and late-night eating in individuals with obesity Full Text

Diet – let food be thy medicine…
*Beer, wine, and spirits differentially influence body composition in older white adults–a United Kingdom Biobank study Full Text
*At risk for diabetes? Cut the carbs, says new study Full Text
*Adherence to dietary guidelines and risk of dementia: a prospective cohort study of 94 184 individuals Full Text

Exercise – if you could bottle the benefits of exercise, it would be the biggest blockbuster drug of all time.
*Activity 'snacks' following meals may help maintain muscle mass Full Text (September 2022)
*Dynamic Resistance Exercise Alters Blood ApoA-I Levels, Inflammatory Markers, and Metabolic Syndrome Markers in Elderly Women Full Text
*Effect Of Exercise on Muscle Mass, Fat Mass, Bone Mass, Muscular Strength and Physical Performance in Community Dwelling Older Adults: Systematic Review and Meta-Analysis 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 Improves Endurance in Older Adults Full Text
Astaxanthin Induces Transcriptomic Responses Associated with Lifespan Extension in Caenorhabditis elegans Full Text
Astaxanthin Is Able to Prevent Alcohol-Induced Dysfunction of Liver Mitochondria 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.
*The effects of curcumin-containing supplements on inflammatory biomarkers in hemodialysis patients: A systematic review and meta-analysis
Effect of Curcumin on Attenuation of Liver Cirrhosis via Genes/Proteins and Pathways: A System Pharmacology Study Full Text
Combination of curcumin and piperine synergistically improves pain-like behaviors in mouse models of pain with no potential CNS side effects Full Text

Fisetin
Reduction of senescent fibro-adipogenic progenitors in progeria-aged muscle by senolytics rescues the function of muscle stem cells Full Text
The neuroprotective effects of fisetin, a natural flavonoid in neurodegenerative diseases: Focus on the role of oxidative stress Full Text
Fisetin Attenuates Arsenic-Induced Hepatic Damage by Improving Biochemical, Inflammatory, Apoptotic, and Histological Profile: In Vivo and In Silico Approach 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 efficacy of exogenous melatonin supplement in ameliorating irritable bowel syndrome severity: A meta-analysis of randomized controlled trials Full Text
*Melatonin’s Benefits and Risks as a Therapy for Sleep Disturbances in the Elderly: Current Insights Full Text

Nicotinamide MonoNucleotide (NMN)
DNA damage contributes to age-associated differences in SARS-CoV-2 infection Full Text
A Narrative Review of Nicotinamide Adenine Dinucleotide (NAD)+ Intermediates Nicotinamide Riboside and Nicotinamide Mononucleotide for Keratinocyte Carcinoma Risk Reduction Full Text
NMN ameliorated radiation induced damage in NRF2-deficient cell and mice via regulating SIRT6 and SIRT7

Nicotinamide Riboside (NR)
Purine nucleoside phosphorylase controls nicotinamide riboside metabolism in mammalian cells Full Text
The use of progeroid DNA repair-deficient mice for assessing anti-aging compounds, illustrating the benefits of nicotinamide riboside Full Text
Low Nephron Number Induced by Maternal Protein Restriction Is Prevented by Nicotinamide Riboside Supplementation Depending on Sirtuin 3 Activation Full Text

Pterostilbene
Pterostilbene Prevents Tunicamycin-Induced Intestinal Barrier Damage by Targeting Endoplasmic Reticulum Stress, Oxidative Stress, Autophagy, and Gut Microbiota

Resveratrol
*Greater habitual resveratrol intakes were associated with lower risk of hip fracture- a 1:1 matched case-control study in Chinese elderly
A meta-analysis of resveratrol protects against cerebral ischemia/reperfusion injury: Evidence from rats studies and insight into molecular mechanisms Full Text
Pharmacological Effects of Resveratrol in Intervertebral Disc Degeneration: A Literature Review Full Text

Spermidine
Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice

Other available supplements & natural substances (in alphabetical order)
*Real-world evidence for the effectiveness of vitamin D supplementation in reduction of total and cause-specific mortality Full Text
*Vitamin D deficiency linked to premature death Abstract
Ginseng and ginsenosides: Therapeutic potential for sarcopenia Full Text
*Effects of L-Citrulline Supplementation on Endothelial Function and Blood Pressure in Hypertensive Postmenopausal Women Full Text
*Effect of a polyphenol-rich dietary supplement containing Pinus massoniana bark extract on blood pressure in healthy adults: A parallel, randomized placebo-controlled trial Full Text
*Quercetin improves lacrimal gland function through its anti-oxidant actions: Evidence from animal studies, and a pilot study in healthy human volunteers Full Text
*Antioxidant Efficacy of a Standardized Red Orange (Citrus sinensis (L.) Osbeck) Extract in Elderly Subjects: A Randomized, Double Blind, Controlled Study Full Text

Combinations of Supplements
Neuroprotective effects of combined therapy with memantine, donepezil, and vitamin D in ovariectomized female mice subjected to dementia model
*Effects of an Omega-3 Supplemented, High-Protein Diet in Combination with Vibration and Resistance Exercise on Muscle Power and Inflammation in Old Adults: A Pilot Randomized Controlled Trial Full Text
Astaxanthin-folic acid combined treatment potentiates neuronal regeneration and functional recovery after brachial plexus avulsion and reimplantation Full Text

Prescription Supplements

Metformin
*The efficacy of vitamin B12 supplementation for treating vitamin B12 deficiency and peripheral neuropathy in metformin-treated type 2 diabetes mellitus patients: A systematic review Full Text
*Reassessing the evidence of a survival advantage in Type 2 diabetes treated with metformin compared with controls without diabetes: a retrospective cohort study
*Metformin Use before Influenza Vaccination May Lower the Risks of Influenza and Related Complications Full Text
*Examining the relationship between metformin dose and cancer survival: A SEER-Medicare analysis Full Text
*Efficacy of metformin therapy in patients with cancer: a meta-analysis of 22 randomised controlled trials Full Text

Rapamycin (sirolimus)
Short-term rapamycin treatment increases life span and attenuates aortic aneurysm in a murine model of Marfan-Syndrome
Rapamycin treatment early in life reprograms aging: hyperfunction theory and clinical practice Full Text
*A mixed blessing for liver transplantation patients — Rapamycin

SGLT-2 Inhibitors
*Cardiovascular and renal efficacy and safety of sodium-glucose cotransporter-2 inhibitors in patients without diabetes: a systematic review and meta-analysis of randomised placebo-controlled trials Full Text
*The role of sodium-glucose co-transporter-2 inhibitors in frail older adults with or without type 2 diabetes mellitus Full Text
*Repurposing SGLT-2 Inhibitors to Target Aging: Available Evidence and Molecular Mechanisms Full Text
*Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis Full Text

Miscellaneous Molecules & Prescription Drugs
MOTS-c, the Most Recent Mitochondrial Derived Peptide in Human Aging and Age-Related Diseases Full Text
Captopril Alleviates Chondrocyte Senescence in DOCA-Salt Hypertensive Rats Associated with Gut Microbiome Alteration Full Text
Neuroprotective effect of low-dose paracetamol treatment against cognitive dysfunction in d-galactose-induced aging mice Full Text

Other Areas of Interest (in alphabetical order)

Ageing Clocks & other biomarkers of ageing
*A machine learning-based data mining in medical examination data: a biological features-based biological age prediction model Full Text
*Marijuana use and DNA methylation-based biological age in young adults Full Text

Blood Factors or other Heterochronic Transplantation
Human Serum Albumin Misfolding in Aging and Disease Full Text
Fetal muscle extract improves muscle function and performance in aged mice Full Text

Epigenetics & Cellular Reprogramming
TBX20 enhances reprogramming of heart fibroblasts into heart muscle cells Full Text
Past, Present, and Future of Direct Cell Reprogramming Full Text

Exosomes (small packets of information released by cells)
Cell-derived vesicles from adipose-derived mesenchymal stem cells ameliorate irradiation-induced salivary gland cell damage Full Text
Mechanical Strain Drives Exosome Production, Function, and miRNA Cargo in C2C12 Muscle Progenitor Cells Full Text

Genetics including CRISPR
*Age vs. genetics: Which is more important for determining how we age? Full Text
*Night vision restored in days after decades of congenital blindness
New technique helps ID genes related to aging Full Text

Lifespan Lengthening Interventions
SIRT3 deficiency decreases oxidative metabolism capacity but increases lifespan in male mice under caloric restriction Full Text
Broccoli Sprouts Promote Sex-Dependent Cardiometabolic Health and Longevity in Long-Evans Rats Full Text
Intestine-specific removal of DAF-2 nearly doubles lifespan in Caenorhabditis elegans with little fitness cost Full Text
Lacticaseibacillus rhamnosus Probio-M9 extends the lifespan of Caenorhabditis elegans Full Text

Microbiome
Regular fecal microbiota transplantation to Senescence Accelerated Mouse-Prone 8 (SAMP8) mice delayed the aging of locomotor and exploration ability by rejuvenating the gut microbiota Full Text

Observational Studies
*Best evidence yet that lowering blood pressure can prevent dementia Full Text
*Preparedness for healthy ageing and polysubstance use in long-term cannabis users: a population-representative longitudinal study Full Text
*Today’s Older Adults Are Cognitively Fitter Than Older Adults Were 20 Years Ago, but When and How They Decline Is No Different Than in the Past Full Text

Opinion/Editorials/Theory
Why Gilgamesh failed: the mechanistic basis of the limits to human lifespan Full Text
We are all aging, and here's why Full Text
Endpoints for geroscience clinical trials: health outcomes, biomarkers, and biologic age Full Text
Does cognitive aging follow an orchid and dandelion phenomenon? Full Text

Other Ageing Biology
Manipulating stress response in cells could help slow down aging Full Text
Multigenerational downregulation of insulin/IGF-1 signaling in adulthood improves lineage survival, reproduction, and fitness in Caenorhabditis elegans supporting the developmental theory of ageing Full Text
mTOR gets greasy: lysosomal sensing of cholesterol Full Text

Regenerative Medicine
Scientists manufacture 'living blood vessel'
Rapid Regeneration of a Neoartery with Elastic Lamellae Full Text

Reproductive Health
Macrophage-derived extracellular vesicles regulate follicular activation and improve ovarian function in old mice by modulating local environment Full Text
Melatonin protects against ovarian damage by inhibiting autophagy in granulosa cells in rats Full Text
Quercetin protects porcine oocytes from in vitro aging by reducing oxidative stress and maintaining the mitochondrial functions Full Text

Reviews
Therapeutic Antiaging Strategies Full Text
ROS: Basic Concepts, Sources, Cellular Signaling, and its Implications in Aging Pathways Full Text
The metabolomics of human aging: Advances, challenges, and opportunities Full Text
Understanding the aging hypothalamus, one cell at a time Full Text

Senolytics/Senescent Cells
Senotherapeutics and Their Molecular Mechanism for Improving Aging Full Text
Reduction of senescent fibro-adipogenic progenitors in progeria-aged muscle by senolytics rescues the function of muscle stem cells Full Text
Senescent cells as vaccines against cancer Full Text

Skin & Beauty
Effects of tocotrienol on aging skin: A systematic review Full Text
*Use of Retinoids in Topical Antiaging Treatments: A Focused Review of Clinical Evidence for Conventional and Nanoformulations Full Text
*Benefits of topical hyaluronic acid for skin quality and signs of skin aging: From literature review to clinical evidence Full Text

Stem Cells
A stem cell aging framework, from mechanisms to interventions Full Text
Human fetal membrane-mesenchymal stromal cells generate functional spinal motor neurons in vitro Full Text

Telomeres
*Three months-longitudinal changes in relative telomere length, blood chemistries, and self-report questionnaires in meditation practitioners compared to novice individuals during midlife Full Text
*Analysis on in vitro effect of lithium on telomere length in lymphoblastoid cell lines from bipolar disorder patients with different clinical response to long-term lithium treatment Full Text

**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 *bolded any human trials.*
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------