August 2022 Longevity Review

Posted by Chris Pollyanna , 10 September 2022 · 1,787 views

supplements rapamycin nmn nad+ epigenetic reprogramming gene therapy health fasting glynac resveratrol

So much for the dog days of summer - after a fallow July, August was a blockbuster month in the longevity field with the first human results for plasma dilution therapy, a placebo controlled trial showing benefits for GlyNAC, and a potential breakthrough for epigenetic reprogramming. And that’s just scratching the surface!

In the supplemental section you’ll also find a couple papers showing synergistic effects when combining senolytics, a novel hair growth method involving rapamycin, some advances with gene therapy, more NMN results, and lots of other human trials.

It’s months like this that give me hope that effective longevity treatments will become available in our lifetimes.

CLA News Chris’s n=1 Rapamycin Trial

No real news from the CLA, as stuff in my personal life kinda took over, but that includes one thing I will talk about: I am embarking on a three month trial of Rapamycin!

This is something I’ve wanted to do for many years and in fact in 2019 went through the trouble of getting a prescription from Dr. Green in NYC and going to Buffalo to fill it out, only to end up getting a mere 36mg, which I ended up giving to my mother.

This time I managed to get hold of 200mg from Turkey via a friend who was travelling there, which is enough for three months at 5mg per week for both myself and my parents. To minimise side effects, I’m starting at 2mg which I will increase by 1mg per week until I hit my regular dose.

As I’m not expecting to “feel” anything from it, I’m trying to gather as many before/after biomarkers as possible. So, I’ve had bloodwork done which I will put into the PhenoAge Calculator and have taken the AgeRate and GlycanAge biological age tests. (Note: I got those for free) I’ve also been wearing a continuous glucose monitor (something else I’ve wanted to do for a long time), though it’s too expensive to do for the duration. I’m also making sure that everything else I do in terms of supplements etc stays the same as much as possible.

I will be sharing my results here, though for more real time updates, check out my Twitter feed.

Canadian Longevity Association

Canadian Longevity Association YouTube Channel - where you can find video talk-throughs of these reviews. (I’ve recorded June & July, but yet to post, which I will do shortly)

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.

August 2022 Round-Up:

This first in human study of plasma dilution, although with only 3 patients, could be quite significant. There has been a lot of discussion over whether beneficial molecules in young blood, or detrimental molecules in old blood are more important. Here, the simple dilution of old plasma, and by extension the reduction in detrimental molecules, had an impressive effect. Even more exciting is the fact that this procedure is already available in some clinics! Larger trials are certainly warranted before you rush to book an apheresis appointment, but certainly something to keep a close eye on.
*Plasma Dilution Appears to Rejuvenate Humans Full Text

Following on from a small pilot study showing that large doses of the combination of glycine and NAC (GlyNAC) improved various aspects of ageing, this new and slightly larger placebo controlled trial replicated the results indicating that GlyNAC “improves and reverses multiple age-associated abnormalities to promote health in aging humans”. This seems such a simple intervention and I am very much looking forward to larger confirmatory trials.
*GlyNAC supplementation reverses aging hallmarks in aging humans Full Text

While digging a little bit deeper, I discovered two earlier trials from this year which I had somehow missed:

*GlyNAC (Glycine and N-Acetylcysteine) Supplementation Improves Impaired Mitochondrial Fuel Oxidation and Lowers Insulin Resistance in Patients with Type 2 Diabetes: Results of a Pilot Study Full Text (Jan 2022)

*A Randomized Controlled Clinical Trial in Healthy Older Adults to Determine Efficacy of Glycine and N-Acetylcysteine Supplementation on Glutathione Redox Status and Oxidative Damage Full Text (March 2022)

The combination of rapamycin and metformin has produced the greatest published life extension for the Interventions Testing Program, and here a further study teases out how they work together synergistically to alleviate each other's potential side effects.
Rapamycin and Metformin Show Synergy in Mice Full Text

As someone who’s been wearing a continuous glucose monitor for the past couple of weeks and seeing the benefit of continuous monitoring, this latest research caught my eye. The more that we know is going on inside our bodies, the more we can do something about it.
*A wearable electrochemical biosensor for the monitoring of metabolites and nutrients Full Text

And finally, ending with a preprint which, if it holds true through peer review, could be game changing. Epigenetic reprogramming is the next “Big Thing” in longevity research, but hitherto involved genetic manipulation. Here, researchers claim to have found a chemical combination which did the same and additionally has greater translational potential to humans.
Two Small Molecules May Provide Partial Reprogramming
Chemical reprogramming ameliorates cellular hallmarks of aging and extends lifespan Full Text

Supplemental Section

Lifestyle

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.
*Time–restricted eating alters the 24-hour profile of adipose tissue transcriptome in men with obesity Full Text
*Epigenome-wide association study analysis of calorie restriction in humans, CALERIE TM Trial analysis Full Text
*A randomized crossover trial assessing time of day snack consumption and resulting postprandial glycemic response in a real-life setting among healthy adults Full Text
*Restricting Eating to Certain Hours Bolsters Weight Loss Abstract

Diet – let food be thy medicine…
*Green tea improves cognitive function through reducing AD-pathology and improving anti-oxidative stress capacity in Chinese middle-aged and elderly people Full Text
*Bottoms Up on Black Tea for a Long Life? Abstract
*Alternative dietary protein sources to support healthy and active skeletal muscle aging Full Text

Exercise – if you could bottle the benefits of exercise, it would be the biggest blockbuster drug of all time.
*Exercise as an Aging Mimetic: A New Perspective on the Mechanisms Behind Exercise as Preventive Medicine Against Age-Related Chronic Disease Full Text
*Exercise answer: Research shows it's how often you do it, not how much Abstract
*Association of Leisure Time Physical Activity Types and Risks of All-Cause, Cardiovascular, and Cancer Mortality Among Older Adults 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 Alleviates Nonalcoholic Fatty Liver Disease by Regulating the Intestinal Flora and Targeting the AMPK/Nrf2 Signal Axis
Biological and neurological activities of astaxanthin (Review) Full Text
Astaxanthin Inhibits Matrix Metalloproteinase Expression by Suppressing PI3K/AKT/mTOR Activation in Helicobacter pylori-Infected Gastric Epithelial Cells 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.
*Curcumin Offers No Additional Benefit to Lifestyle Intervention on Cardiometabolic Status in Patients with Non-Alcoholic Fatty Liver Disease Full Text
*Therapeutic Role of Curcumin in Diabetes: An Analysis Based on Bioinformatic Findings Full Text
*Curcumin and Curcuma longa Extract in the Treatment of 10 Types of Autoimmune Diseases: A Systematic Review and Meta-Analysis of 31 Randomized Controlled Trials Full Text

Fisetin
Therapeutic targeting of mechanical stretch-induced FAK/ERK signaling by fisetin in hypertrophic scars

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.
Melatonin alleviates renal injury by activating mitophagy in diabetic nephropathy Full Text
Melatonin Alleviates Acute Kidney Injury by Inhibiting NRF2/Slc7a11 Axis-Mediated Ferroptosis Full Text
Melatonin promotes sirtuin 1 expression and inhibits IRE1α–XBP1S–CHOP to reduce endoplasmic reticulum stress–mediated apoptosis in chondrocytes Full Text

Nicotinamide MonoNucleotide (NMN)
Quantitative acetylomics reveals dynamics of protein lysine acetylation in mouse livers during aging and upon the treatment of nicotinamide mononucleotide Full Text
*Safety evaluation of β-nicotinamide mononucleotide oral administration in healthy adult men and women Full Text
*Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men Full Text (May 2022)
Nicotinamide mononucleotide alleviates osteoblast senescence induction and promotes bone healing in osteoporotic mice

Nicotinamide Riboside (NR)
Nicotinamide Riboside alleviates exercise intolerance in ANT1-deficient mice Full Text
Balancing NAD+ deficits with nicotinamide riboside: therapeutic possibilities and limitations Full Text
*A randomized placebo-controlled trial of nicotinamide riboside+pterostilbene supplementation in experimental muscle injury in elderly subjects Full Text

Pterostilbene
Pterostilbene attenuates intestinal epithelial barrier loss induced by high loading intensity of exercise Full Text
Pterostilbene inhibits melanogenesis, melanocyte dendricity and melanosome transport through cAMP/PKA/CREB pathway Full Text

Resveratrol
*Effects of resveratrol therapy on glucose metabolism, insulin resistance, inflammation, and renal function in the elderly patients with type 2 diabetes mellitus: A randomized controlled clinical trial protocol Full Text
*Influence of Age and Dose on the Effect of Resveratrol for Glycemic Control in Type 2 Diabetes Mellitus: Systematic Review and Meta-Analysis Full Text
Insights into the Anti-inflammatory and Antiviral Mechanisms of Resveratrol Full Text

Spermidine
*Non-linear association between serum spermidine and mild cognitive impairment: Results from a cross-sectional and longitudinal study Full Text
A systematic exploration reveals the potential of spermidine for hypopigmentation treatment through the stabilization of melanogenesis-associated proteins Full Text
Effects of Spermidine on Gut Microbiota Modulation in Experimental Abdominal Aortic Aneurysm Mice Full Text

Other available supplements (in alphabetical order)
*Acetyl-L-carnitine can slow the progression from prefrailty to frailty in older subjects. A randomized interventional clinical trial
*B vitamins can potentially be used to treat advanced non-alcoholic fatty liver disease Full Text (July 2022)
*Association Between Beta-Carotene Supplementation and Mortality: A Systematic Review and Meta-Analysis of Randomized Controlled Trials Full Text (July 2022)
*Effects of creatine supplementation on memory in healthy individuals: a systematic review and meta-analysis of randomized controlled trials
*Association of vitamin E intake in diet and supplements with risk of dementia: A meta-analysis Full Text
Menaquinone-7 ameliorates cerebrovascular calcification-associated memory decline in aged mice
*Efficacy of the omega-3 fatty acids supplementation on inflammatory biomarkers: An umbrella meta-analysis (July 2022)
*Omega-3 Fatty Acids for the Management of Osteoarthritis: A Narrative Review Full Text
Omega-3 polyunsaturated fatty acids reverse the impact of western diets on regulatory T cell responses through averting ceramide-mediated pathways Full Text

Combinations of Supplements
*Combined treatment with Ginkgo biloba extract EGb 761 plus acetylcholinesterase inhibitors improved cognitive function and neuropsychiatric symptoms in patients with mild cognitive impairment Full Text
Improvement of tissue-specific distribution and biotransformation potential of nicotinamide mononucleotide in combination with ginsenosides or resveratrol Full Text (July 2022)
*Choroidal Changes in Blood Flow in Patients with Intermediate AMD after Oral Dietary Supplement Based on Astaxanthin, Bromelain, Vitamin D3, Folic Acid, Lutein, and Antioxidants Full Text
*Selenium and Coenzyme Q10 Intervention Prevents Telomere Attrition, with Association to Reduced Cardiovascular Mortality—Sub-Study of a Randomized Clinical Trial Full Text
*'Polypill' reduces cardiovascular mortality by 33% in patients treated after a heart attack Abstract

Prescription Supplements

Metformin
The Protective Action of Metformin against Pro-Inflammatory Cytokine-Induced Human Islet Cell Damage and the Mechanisms Involved Full Text
Metformin attenuates osteoarthritis by targeting chondrocytes, synovial macrophages and adipocytes
Regulatory Effects of Metformin, an Antidiabetic Biguanide Drug, on the Metabolism of Primary Rat Adipocytes Full Text

Rapamycin (sirolimus)
Brief Rapamycin Treatment in Early Adulthood Combats Aging Full Text Researchers Video
mTOR Complex 1 Content and Regulation Is Adapted to Animal Longevity Full Text
Overview of Research into mTOR Inhibitors Full Text
*Randomized Trial of Early mTOR Inhibition in Patients with Acute ST-Segment Elevation Myocardial Infarction

Miscellaneous Molecules & Prescription Drugs
Suppression of trimethylamine N-oxide with DMB mitigates vascular dysfunction, exercise intolerance, and frailty associated with a Western-style diet in mice
Canagliflozin Alleviates Several Aging Pathologies in Mice Full Text
*SGLT2-inhibitors are Effective and Safe in the Elderly: the SOLD Study
Empagliflozin improves cardiac mitochondrial function and survival through energy regulation in a murine model of heart failure

Other Areas of Interest (in alphabetical order)

Ageing Clocks & other biomarkers of ageing
*Deep learning predicts all-cause mortality from longitudinal total-body DXA imaging Full Text
*How alcohol makes the epigenetic clock tick faster and the clock reversing effect of abstinence Full Text (June 2022)
*Inflammation and epigenetic ageing are largely independent markers of biological ageing and mortality Full Text

Blood Factors or other Heterochronic Transplantation
Three Month Heterochronic Parabiosis Has a Deleterious Effect on the Lifespan of Young Animals, Without a Positive Effect for Old Animals Full Text
The effect of young blood plasma administration on gut microbiota in middle-aged rats

Exosomes (small packets of information released by cells)
Diagnostic and Therapeutic Roles of Extracellular Vesicles in Aging-Related Diseases Full Text
*Association of extracellular vesicle inflammatory proteins and mortality Full Text
Mesenchymal Stem Cell-Derived Small Extracellular Vesicles: A Novel Approach for Kidney Disease Treatment Full Text

Genetics including CRISPR
*Identifying Mitonuclear Genes for Longevity Full Text
New gene therapy shows promise for treating eye condition affecting millions across the globe Full Text
Gene therapy approach shows promise in treating ALS Full Text
*New gene therapy could block bad cholesterol

Lifespan Lengthening Interventions
Lactiplantibacillus plantarum Strain FLPL05 Promotes Longevity in Mice by Improving Intestinal Barrier
MyMD-1 improves health span and prolongs lifespan in old mice: A non-inferiority study to rapamycin
Soluble guanylate cyclase activator BAY 54–6544 improves vasomotor function and survival in an accelerated ageing mouse model Full Text
CeO2 nanoparticles improve prooxidant/antioxidant balance, life quality and survival of old male rats
Disruption of growth hormone receptor in adipocytes improves insulin sensitivity and lifespan in mice

Microbiome
*Fecal microbiota transplantation can improve cognition in patients with cognitive decline and Clostridioides difficile infection Full Text
*Zero-Calorie Sweeteners Alter the Human Microbiome Full Text
*The Effects of Physical Activity on the Gut Microbiota and the Gut–Brain Axis in Preclinical and Human Models: A Narrative Review Full Text

Observational Studies
*Associations of bioavailable serum testosterone with cognitive function in older men: results from the National Health and Nutrition Examination Survey Full Text
*The Impact of Education and Lifestyle Factors on Disability-Free Life Expectancy From Mid-Life to Older Age: A Multi-Cohort Study Full Text
*Cumulative loneliness and subsequent memory function and rate of decline among adults aged ≥50 in the United States, 1996 to 2016 Full Text

Opinion/Editorials/Theory
Researchers Propose Five New Hallmarks of Aging Full Text
New horizons in life extension, healthspan extension and exceptional longevity Full Text
A complex systems approach to aging biology Full Text (July 2022)

Other Ageing Biology
Construction of a cross-species cell landscape at single-cell level Full Text
Targeting SIRT1 Rescues Age- and Obesity-Induced Microvascular Dysfunction in Ex Vivo Human Vessels Full Text
Artificially stimulating retrotransposon activity increases mortality and accelerates a subset of aging phenotypes in Drosophila Full Text

Regenerative Medicine
Advancement of Organoid Technology in Regenerative Medicine Full Text
Rotator cuff regeneration: potential breakthrough treatment Abstract
*Bioengineered cornea can restore sight to the blind and visually impaired Full Text

Reproductive Health
*The role of testosterone in male sexual function Full Text
hUCMSCs reduce theca interstitial cells apoptosis and restore ovarian function in premature ovarian insufficiency rats through regulating NR4A1-mediated mitochondrial mechanisms Full Text
Aging conundrum: A perspective for ovarian aging Full Text

Reviews
Epigenetics, DNA damage, and aging Full Text
A gut-centric view of aging: Do intestinal epithelial cells contribute to age-associated microbiota changes, inflammaging, and immunosenescence? Full Text
Immunosenescence, aging and successful aging Full Text
A Review on Peripheral Tinnitus, Causes, and Treatments from the Perspective of Autophagy Full Text

Senolytics/Senescent Cells
Combining Senolytic Pathways Has Synergistic Effects Full Text
Cellular senescence and senolytics: the path to the clinic Full text
Senolytic drugs relieve pain by reducing peripheral nociceptive signaling without modifying joint tissue damage in spontaneous osteoarthritis Full Text

Skin & Beauty
Exosomes Derived from Secretome Human Umbilical Vein Endothelial Cells (Exo-HUVEC) Ameliorate the Photo-Aging of Skin Fibroblast Full Text (with video)
Rapamycin-Loaded Microneedles Reverse Hair Loss in Mice Full Text (July 2022)
Pgc-1α controls epidermal stem cell fate and skin repair by sustaining NAD+ homeostasis during aging Full Text

Stem Cells
Intravenous Stem Cells Alleviate Guinea Pig Osteoarthritis Abstract
Stem cell-based therapy for human diseases Full Text
Aging of mesenchymal stem cell: machinery, markers, and strategies of fighting Full Text

Telomeres
*Genetically predicted telomere length and its relationship with neurodegenerative diseases and life expectancy Full Text
*C-peptide is a predictor of telomere shortening: A five-year longitudinal study 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.*
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