September 2022 Longevity Review

Posted by Chris Pollyanna , 17 October 2022 · 1,098 views

supplements rapamycin metformin nad+ nmn reseveratrol curcumin fasting

After last month’s blockbuster, there was a slight slowdown in the longevity field as the summer wound down and the leaves contemplated their journey earthwards. As a counterpoint to August’s plasma dilution lead item, a study came out this month showing the reverse with the use of umbilical cord plasma concentrate giving a small reduction in GrimAge. Vying for top spot was the largest extension of mouse lifespan yet published as the Interventions Testing Program’s (ITP) latest tranche of results came out. And rounding out the Round-Up, you’ll find three studies which used a multi-supplement approach to provide benefits for older adults.

On a personal note, it’s been a difficult past few weeks as my mother came down with and was hospitalized for covid while we were visiting relatives in Munich. What should have been a three night stay turned into fifteen. Fortunately, she has fully recovered, no small part due to the excellent level of care in Munich, all of it free of course via the European health card. Needless to say, I’ve been rather distracted and hence the delay in getting this newsletter out this month.

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CLA News Chris’s n=1 Rapamycin Trial

Since starting my rapamycin trial at the beginning of September, I’ve ramped up my weekly dose to 5mg, which I've taken three times now.

As expected, I’ve not noticed anything so far, including any side effects.

I also received the results of my baseline biological age tests, which were quite variable. Due to the circumstances, I’ve not had the chance to dig into the results. Both AgeRate and GlycanAge produce detailed breakdowns of your score and GlycanAge additionally offers a 30 minute consultation, which I have not had yet.

My chronological age at the time of these tests was 46.5 years young.

AgeRate’s epigenetic test gave me a biological age of 45.

The Levine phenotypic age calculator based on blood work gave me an age of 41.1 (a link to the spreadsheet used - I did not produce this)

While the GlycanAge test said I had a biological age of 22! (I really need to have that free consultation… )

It will be interesting to see if and by how much any of these change after 12 weeks on rapamycin.

September 2022 Round-Up:

This small safety study using weekly injection of umbilical cord plasma concentrate for ten weeks in 18 individuals resulted in the improvement of 20 clinical biomarkers as well as a small reduction in GrimAge, which assesses mortality risk. This indicates that there are potentially youthful factors in young plasma.

When these results are taken in conjunction with the benefits shown by plasma dilution, it lends credence to my belief that it will be the combination of the removal of ageing factors and the addition of youthful factors that will produce the greatest boon for longevity. I look forward to further larger studies which will hopefully combine the two approaches.
*Umbilical Plasma Injections Reduce Biological Age in Humans Full Text

The latest ITP results have finally been released, with the combination of Rapamycin and Acarbose showing the greatest lifespan extension seen in mice so far - a 28% and 34% increase in median lifespan for female and male mice respectively. This would roughly equate to an additional 25 years for humans if there was a direct translation!

Additionally, Captopril increased median lifespan in female & male mice by 6% and 13% respectively. All the other molecules tested did not significantly affect lifespan.
Combination of Rapamycin and Acarbose Extends Lifespan Full Text

I wanted to highlight three studies which fell within my favourite topic: the combination of treatments, or in this case supplements. The three trials used different combinations, including one of a commercially available multivitamin, and were testing for different outcomes, however all seemed to demonstrate a benefit.

*Multivitamin Supplementation Shown to Improve Cognition Full Text

*Natural Activators of Autophagy Increase Maximal Walking Distance and Reduce Oxidative Stress in Patients with Peripheral Artery Disease: A Pilot Study Full Text

*Use of Nutraceuticals in Elderly to Fight Inflammation and Immuno-Senescence: A Randomized Case-Control Study Full Text (August 2022)

Supplemental Section

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.
*Timing of daily calorie loading affects appetite and hunger responses without changes in energy metabolism in healthy subjects with obesity Full Text
*Fasting-mimicking diet cycles reduce neuroinflammation to attenuate cognitive decline in Alzheimer’s models Full Text
*Intermittent fasting positively modulates human gut microbial diversity and ameliorates blood lipid profile Full Text (August 2022)

Diet – let food be thy medicine…
*How does what we eat affect our healthspan and longevity? It's a complex dynamic system Full Text
*Adherence to a Healthy Beverage Score Is Associated with Lower Frailty Risk in Older Adults Full Text
*Six-month intervention with wild blueberries improved speed of processing in mild cognitive decline: a double-blind, placebo-controlled, randomized clinical trial Full Text

Exercise – if you could bottle the benefits of exercise, it would be the biggest blockbuster drug of all time.
Exercise training maintains cardiovascular health: signaling pathways involved and potential therapeutics Full Text
*The non-modifiable factors age, gender, and genetics influence resistance exercise Full Text
*Prospective Associations of Daily Step Counts and Intensity With Cancer and Cardiovascular Disease Incidence and Mortality and All-Cause Mortality 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 attenuates osteoarthritis progression via inhibiting ferroptosis and regulating mitochondrial function in chondrocytes
Dietary astaxanthin-rich extract ameliorates atherosclerosis/retinopathy and restructures gut microbiome in apolipoprotein E-deficient mice fed on a high-fat diet

Curcumin – the spice which gives curries their yellow colour. Anti-inflammatory and neuroprotective. Needs to be taken with black pepper (piperine) to improve bioavailability.
*Micellar Curcumin: Pharmacokinetics and Effects on Inflammation Markers and PCSK-9 Concentrations in Healthy Subjects in a Double-Blind, Randomized, Active-Controlled, Crossover Trial Full Text
*Curcumin supplementation reduces blood glucose and serum lipids of Brazilian women with high waist circumference: a randomized clinical trial Full Text
*Effects of high-absorption curcumin for the prevention of hypertensive heart disease: a double-blind, placebo-controlled, randomized clinical study 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.
*Melatonin supplementation alleviates cellular damage and physical performance decline induced by an intensive training period in professional soccer players Full Text
*Effect of melatonin on quality of life and symptoms in patients with cancer: a systematic review and meta-analysis of randomised controlled trials Full Text
*The effects of daytime melatonin ingestion on arousal and vigilance vanish after sub-maximal exercise: a pilot study Full Text

Nicotinamide MonoNucleotide (NMN)
Declining muscle NAD+ in a hyperandrogenism PCOS mouse model: Possible role in metabolic dysregulation Full Text
Treatment of inflammatory bowel disease: Potential effect of NMN on intestinal barrier and gut microbiota Full Text

Nicotinamide Riboside (NR)
*NRPT reduces markers of hepatic inflammation in non-alcoholic fatty liver disease: a double-blind, placebo-controlled clinical trial
Nicotinamide riboside kinase 1 protects against diet and age-induced pancreatic β-cell failure Full Text
Nicotinamide adenine dinucleotide supplementation drives gut microbiota variation in Alzheimer’s mouse model Full Text

Pterostilbene
Improved oral nutraceutical-based intervention for the management of obesity: pterostilbene-loaded chitosan nanoparticles
Pterostilbene improves CFA-induced arthritis and peripheral neuropathy through modulation of oxidative stress, inflammatory cytokines and neurotransmitters in Wistar rats
Pterostilbene Fails to Rescue Insulin Secretion and Sensitivity in Multiple Murine Models of Diabetes Full Text

Resveratrol
*The Effect of Resveratrol on Blood Lipid Profile: A Dose-Response Meta-Analysis of Randomized Controlled Trials Full Text
*Exosome-Containing Extracellular Vesicles Contribute to the Transport of Resveratrol Metabolites in the Bloodstream: A Human Pharmacokinetic Study Full Text
Resveratrol protection against IL-1β-induced chondrocyte damage via the SIRT1/FOXO1 signaling pathway Full Text

Spermidine
*Association between Serum Spermidine and TyG Index: Results from a Cross-Sectional Study Full Text

Other available supplements (in alphabetical order)
The potential of Ginkgo biloba in the treatment of human diseases and the relationship to Nrf2–mediated antioxidant protection Full Text
Ginsenoside and Its Therapeutic Potential for Cognitive Impairment Full Text
Long-term administration of red ginseng non-saponin fraction rescues the loss of skeletal muscle mass and strength associated with aging in mice Full Text
The Therapeutic Relevance of Urolithins, Intestinal Metabolites of Ellagitannin-Rich Food: A Systematic Review of In Vivo Studies Full Text (August 2022)

Combinations of Supplements
*Effects of a combination of resveratrol and alpha-lipoic acid on body weight and adipose composition in women with PCOS: a preliminary pilot study Full Text
*δ-Tocotrienol in Combination with Resveratrol Improves the Cardiometabolic Risk Factors and Biomarkers in Patients with Metabolic Syndrome: A Randomized Controlled Trial
*A 2-year randomized controlled trial with low-dose B-vitamin supplementation shows benefits on bone mineral density in adults with lower B12 status Full Text

Prescription Supplements

Metformin
*Effect of metformin on left ventricular mass and functional parameters in non-diabetic patients: a meta-analysis of randomized clinical trials Full Text
*Comparative effect of metformin versus sulfonylureas with dementia and Parkinson’s disease risk in US patients over 50 with type 2 diabetes mellitus Full Text
Effectiveness and mechanism of metformin in animal models of pulmonary fibrosis: A preclinical systematic review and meta-analysis Full Text

Rapamycin (sirolimus)
Rapamycin treatment during development extends life span and health span of male mice and Daphnia magna Full Text
Long-term treatment with low dose rapamycin extends lifespan and delays tumours in cancer-prone germline PTEN mutant mice
Pharmacological mTOR-inhibition facilitates clearance of AD-related tau aggregates in the mouse brain

Miscellaneous Molecules & Prescription Drugs
*Impact of SGLT2 inhibitors on old age patients with heart failure and chronic kidney disease

Other Areas of Interest (in alphabetical order)

Ageing Clocks & other biomarkers of ageing
*Beyond chronological age: a multidimensional approach to survival prediction in older adults Full Text
*A new cognitive clock matching phenotypic and epigenetic ages Full Text
*Metabolomic profiles predict individual multidisease outcomes Full Text
*Psychological factors substantially contribute to biological aging: evidence from the aging rate in Chinese older adults Full Text

Blood Factors or other Heterochronic Transplantation
Young bone marrow transplantation prevents aging-related muscle atrophy in a senescence-accelerated mouse prone 10 model Full Text
Young plasma reverses anesthesia and surgery-induced cognitive impairment in aged rats by modulating hippocampal synaptic plasticity Full Text

Epigenetics & Cellular Reprogramming
Aging and cancer epigenetics: Where do the paths fork? Full Text
G-quadruplexes Mark Sites of Methylation Instability Associated with Ageing and Cancer Full Text

Exosomes (small packets of information released by cells)
Systemic proteomics and miRNA profile analysis of exosomes derived from human pluripotent stem cells Full Text
Fndc5/irisin-enriched extracellular vesicles: a new hormonal relay in the regular race against vascular ageing Full Text

Genetics including CRISPR
*Long-Lived Individuals Show a Lower Burden of Variants Predisposing to Age-Related Diseases and a Higher Polygenic Longevity Score Full Text
Clusters of genes help mice live longer The genetics of a long life Full Text
Shared genetic architecture between the two neurodegenerative diseases: Alzheimer’s disease and glaucoma Full Text

Lifespan Lengthening Interventions
A moderate static magnetic field promotes C. elegans longevity through cytochrome P450s Full Text
Longevity-promoting properties of ginger extract in Caenorhabditis elegans via the insulin/IGF-1 signaling pathway
Antiaging effect of anthocyanin extracts from bilberry on natural or UV-treated male Drosophila melanogaster Full Text
Model yeast as a versatile tool to examine the antioxidant and anti-ageing potential of flavonoids, extracted from medicinal plants Full Text

Microbiome
*The Use of Gut Microbial Modulation Strategies as Interventional Strategies for Ageing Full Text
*Short- and Long-Term Effects of a Prebiotic Intervention with Polyphenols Extracted from European Black Elderberry—Sustained Expansion of Akkermansia spp. Full Text
Microbiota alteration and modulation in Alzheimer's disease by gerobiotics: The gut-health axis for a good mind Full Text

Observational Studies
*Association between inflammatory biomarkers and cognitive aging Full Text
*Life-course exposure to air pollution and biological ageing in the Lothian Birth Cohort 1936 Full Text
*Ideal Life’s Simple 7 Score Relates to Macrovascular Structure and Function in the Healthy Population Full Text
*Causal analysis identifies small HDL particles and physical activity as key determinants of longevity of older adults Full Text

Opinion/Editorials/Theory
Sexual activity and successful aging Full Text
Could aging evolve as a pathogen control strategy?

Other Ageing Biology
Meiotic dysfunction accelerates somatic aging in Caenorhabditis elegans Full Text
A hierarchical process model links behavioral aging and lifespan in C. elegans Full Text
A phosphoinositide signalling pathway mediates rapid lysosomal repair Full Text

Reproductive Health
Metformin prevents age-associated ovarian fibrosis by modulating the immune landscape in female mice Full Text
*Age-associated epigenetic changes in mammalian sperm: implications for offspring health and development Full Text
Oocyte mitophagy is critical for extended reproductive longevity Full Text

Reviews
The landscape of aging Full Text (100 page PDF!)
Molecular inhibition of RAS signalling to target ageing and age-related health Full Text
Control of aging by the renin–angiotensin system: a review of C. elegans, Drosophila, and mammals Full Text
What Do We Know about Social and Non-Social Factors Influencing the Pathway from Cognitive Health to Dementia? A Systematic Review of Reviews Full Text

Senolytics/Senescent Cells
Removing Senescent Cells to Alleviate Muscular Dystrophy Full Text
Removing Senescent Cells Improves the Brains of Female Mice
Rejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance Full Text
Pharmacological clearance of senescent cells improves cardiac remodeling and function after myocardial infarction in female aged mice
Is “cellular senescence” a misnomer? Full Text

Skin & Beauty
Autologous platelet concentrates for facial rejuvenation Full Text
In Vivo Skin Regeneration and Wound Healing Using Cell Micro-Transplantation Full Text
Multi-omics analysis of an in vitro photoaging model and protective effect of umbilical cord mesenchymal stem cell-conditioned medium Full Text

Stem Cells
The therapeutic prospects and challenges of human neural stem cells for the treatment of Alzheimer's Disease Full Text
Sequestration of Inflammation in Parkinson’s Disease via Stem Cell Therapy Full Text
Regenerative Effect of Umbilical Cord-Derived Mesenchymal Stromal Cells in a Rat Model of Established Limb Ischemia Full Text

Telomeres
New mechanism extends life of immune system Abstract
*Effect of Omega-3 Fatty Acids on Telomeres—Are They the Elixir of Youth? Full Text
*Physical Activity on Telomere Length as a Biomarker for Aging: A Systematic Review 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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