March 2023 Longevity Review

As Toronto basks in some unseasonably warm weather, we are reminded that Spring is a time for rebirth and renewal and is the perfect season to make some lifestyle changes to improve your longevity. Just as well then that the Round-Up section contains a number of studies to help with that, starting with how such lifestyle changes can reduce your epigenetic age, followed by mortality and disease risk reductions from a good diet, and the benefits of more exercise - though one study shows we can get most of the benefit from doing less than you might think.
Outside the Round-Up there are some comprehensive reviews of the supplements alpha-ketoglutarate, ashwagandha and glycine as well as an analysis of the bioavailability of different curcumin supplements from clinical studies, which is leading me to reconsider how I take it. Further human studies include probiotics for reduced inflammation and Colostrinin for improved cognitive function. There is also a very good review of cellular rejuvenation and in Opinions an interesting look at ageing as a software design flaw. Plus of course much more!

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Chris’s n=1 Rapamycin Trial

I finally received all of my “after” results for my three month 5mg/week rapamycin trial which finished in December, and what a mixed bag they were! Note: my chronological age went from 46.5 to 46.75 over the course of this trial, and I did not “notice” anything or have any side effects.

Starting with the very positive, my PhenoAge, based on 9 blood biomarkers, went from 41.1 to 35.7, which I was obviously quite pleased about. It also intrigued my doctor, who noticed that each marker dealt with a different organ system and moved in a positive direction.

Next, my scarcely believable GlycanAge went from 22 to 23. I still haven’t had a chance to organise the free consultation they offer, but hopefully I will get more info about what this means soon.

Unfortunately, the last result, my epigenetic AgeRate result, was the most disappointing, as my age went from 45 to 48.1! Again, I haven’t had the chance yet to follow this up.

What does this all mean? I have no idea! Except that it is probably still early days when it comes to measuring your biological age. In due course these tests will start to align and accurately measure your ageing rate.

My biggest takeaway from this trial was a greater appreciation on how difficult it is to run clinical trials and why it is important to have very large numbers of people participate to get some statistical significance. I tried to keep everything the same for three months, apart from the addition of rapamycin, but that proved to be impossible. Life has a habit of getting in the way of the best laid plans. Holidays, travel and acutely stressful events precluded healthy consistency.

As for whether or not rapamycin affects human ageing - I now eagerly await the results of large randomised controlled trials, but would happily try it again, though perhaps with the addition of acarbose to help with glucose regulation. Based on all the other preclinical and clinical evidence, I still believe that rapamycin is the longevity drug closest to prime time, but my own n=1 result did not provide a conclusive slam dunk.

March 2023 Round-Up:

This very small case study showed an average 4.6 year epigenetic age reduction in women after following an 8-week dietary and lifestyle intervention. This follows a previous study in men which had similar results. The dietary and lifestyle changes are not too onerous and readily achievable.
*Diet/lifestyle program reverses biological age: A female case series Full Text

Following on from the above dietary and lifestyle intervention, I wanted to reinforce the importance of a good diet for longevity by highlighting three new studies which normally would just have been put in the diet section. In order, they show a 23% reduction in dementia risk, a 25% reduction in mortality and cardiovascular disease for women, and a >20% reduction in chronic diseases for those who more closely follow healthy diets, particularly a Mediterranean one.
*Mediterranean diet associated with decreased risk of dementia Full Text
*Mediterranean diet cuts women's cardiovascular disease and death risk by nearly 25%, finds study Abstract
*Adhering to recommended diets lowers risk of chronic diseases, 32-year study finds Abstract

After looking at the benefits of a good diet, it behooves us not to forget the benefits of exercise as well, with the first study showing that substituting sedentary time with walking/cycling or MVPA reduces phenotypic age acceleration (with the opposite accelerating it), while the second study shows that simply achieving 8000 steps a day once or twice a week has a substantial effect on mortality, with a 15% reduction.
*Associations of sleeping, sedentary and physical activity with phenotypic age acceleration: a cross-sectional isotemporal substitution model Full Text
*Daily Step Count, Less Mortality, Diminishing Returns Full Text

Moving on to supplements, in this small sub-study the combination of selenium and coenzyme Q10 significantly raised levels of SIRT1, a pro-longevity gene, and reduced cardiovascular mortality by almost 50% over a four year period. Though beware that too much selenium can cause toxicity.
*Increased SIRT1 Concentration Following Four Years of Selenium and Q10 Intervention Associated with Reduced Cardiovascular Mortality at 10-Year Follow-Up—Sub-Study of a Previous Prospective Double-Blind Placebo-Controlled Randomized Clinical Trial Full Text

And finally, Sarcopenia, or muscle wasting, is an increasing burden the older you get and although exercise can counteract it, that quite often is not achievable. Here, researchers used gene therapy to increase Neurotrophin 3 in mice which “unequivocally improved the function of sarcopenic muscle, increased muscle fiber size, myelin thickness and NMJ connectivity”. As gene therapy continues to improve, this could be a viable option to prevent sarcopenia in the future.
AAV1.NT-3 gene therapy prevents age-related sarcopenia Full Text

Supplemental Section

Lifestyle
*Healthy lifestyles and wellbeing reduce neuroinflammation and prevent neurodegenerative and psychiatric disorders Full Text (Feb 2023)
*Healthy lifestyle behaviors and biological aging in the US National Health and Nutrition Examination Surveys 1999-2018

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.
*The Health-Promoting Effects and the Mechanism of Intermittent Fasting Full Text
*Cut Calories, Lengthen Life Span? Randomized Trial Uncovers Evidence That Calorie Restriction Might Slow Aging, but Questions Remain Full Text

Exercise – if you could bottle the benefits of exercise, it would be the biggest blockbuster drug of all time.
*Long-Term Resistance Exercise Increases Autophagy Full Text
Autophagy regulates the release of exercise factors and their beneficial effects on spatial memory recall 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, a Natural Antioxidant, Lowers Cholesterol and Markers of Cardiovascular Risk in Individuals with Prediabetes and Dyslipidemia
Smokers Shows Potential Risks of Disease Caused by Oxidative Stress and Inflammation and the Potentiality of Astaxanthin as an Anti-Inflammatory Agent Full Text
Astaxanthin as a King of Ketocarotenoids: Structure, Synthesis, Accumulation, Bioavailability and Antioxidant Properties 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 Formulations for Better Bioavailability: What We Learned from Clinical Trials Thus Far? Full Text
*Effects of Highly Bioavailable Curcumin Supplementation on Common Cold Symptoms and Immune and Inflammatory Functions in Healthy Japanese Subjects: A Randomized Controlled Study Full Text
*The Effect of Curcumin Supplementation on Weight Loss and Anthropometric Indices: An Umbrella Review and Updated Meta-analyses of Randomized Controlled Trials Full Text
*Cardioprotective effects of curcumin against myocardial I/R injury: A systematic review and meta-analysis of preclinical and clinical studies Full Text
*Curcumin effects on chronic obstructive pulmonary disease: A systematic review Full Text

Fisetin
Tubular cell senescence promotes maladaptive kidney repair and chronic kidney disease after cisplatin nephrotoxicity Full Text
Fisetin, a Natural Polyphenol, Ameliorates Endometriosis Modulating Mast Cells Derived NLRP-3 Inflammasome Pathway and Oxidative Stress 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.
*Influence of Acute Melatonin Administration on Human Physical Performance: A Systematic Review
Benefits of the Neurogenic Potential of Melatonin for Treating Neurological and Neuropsychiatric Disorders Full Text
Chronic Administration of Melatonin: Physiological and Clinical Considerations Full Text

Nicotinamide MonoNucleotide (NMN)
NAD+ precursor supplementation prevents mtRNA/RIG-I-dependent inflammation during kidney injury Full Text

Nicotinamide Riboside (NR)
Nicotinamide Adenine Dinucleotide Precursor Suppresses Hepatocellular Cancer Progression in Mice Full Text
Dietary supplementation with nicotinamide riboside improves fetal growth under hypoglycemia Full Text

Resveratrol
*Impact of resveratrol supplementation on clinical parameters and inflammatory markers in patients with chronic periodontitis: a randomized clinical trial Full Text
*Resveratrol may mildly improve renal function in the general adult population: A systematic review and meta-analysis of randomized controlled clinical trials
Therapeutic effects of resveratrol and Omega-3 in mice atherosclerosis: focus on histopathological changes Full Text

Spermidine
Spermidine dietary supplementation and polyamines level in reference to survival and lifespan of honey bees Full Text
Exogenous spermidine alleviates diabetic cardiomyopathy via suppressing ROS, ERS and Pannexin-1-mediated ferroptosis Full Text
Spermidine ameliorates colitis via induction of anti-inflammatory macrophages and prevention of intestinal dysbiosis Full Text

Other available supplements (in alphabetical order)
The physiological metabolite α-ketoglutarate ameliorates osteoarthritis by regulating mitophagy and oxidative stress Full Text
Alpha-ketoglutarate as a potent regulator for lifespan and healthspan: Evidences and perspectives Full Text
Ashwagandha (Withania somnifera)—Current Research on the Health-Promoting Activities: A Narrative Review Full Text
Coenzyme Q10 supplementation improves the motor function of middle-aged mice by restoring the neuronal activity of the motor cortex Full Text
*Proline-rich polypeptides (Colostrinin®/COLOCO®) modulate BDNF concentration in blood affecting cognitive function in adults: A double-blind randomized placebo-controlled study Full Text
*Taking vitamin D could help prevent dementia Full Text
Vitamin D as a Shield against Aging Full Text
*Supplementation with Flaxseed Oil Rich in Alpha-Linolenic Acid Improves Verbal Fluency in Healthy Older Adults Full Text
*Effectiveness and safety of ginkgo biloba preparations in the treatment of Alzheimer's disease: A systematic review and meta-analysis Full Text
*Oral Glucosamine in the Treatment of Temporomandibular Joint Osteoarthritis: A Systematic Review Full Text
Glycine and aging: Evidence and mechanisms Full Text
Hesperetin treatment attenuates glycation of lens proteins and advanced‑glycation end products generation Full Text
*Impact of lithium on mortality among older adults with major psychiatric disorders: A 5-year prospective multicenter study
*A higher dose of magnesium each day keeps dementia at bay Full Text
*Association between Serum Magnesium and Fractures: A Systematic Review and Meta-Analysis of Observational Studies Full Text
Potential of Urolithin A to improve joint health Full Text

Combinations of Supplements
*Effects of Astaxanthin, Lutein, and Zeaxanthin on Eye–Hand Coordination and Smooth-Pursuit Eye Movement after Visual Display Terminal Operation in Healthy Subjects: A Randomized, Double-Blind Placebo-Controlled Intergroup Trial Full Text

Prescription Supplements

Metformin
*Significant impact of time-of-day variation on metformin pharmacokinetics Full Text
*Metformin Monotherapy Alters the Human Plasma Lipidome Independent of Clinical Markers of Glycemic Control and Cardiovascular Disease Risk in a Type 2 Diabetes Clinical Cohort Full Text
*Adherence to antidiabetic drug therapy and reduction of fatal events in elderly frail patients Full Text

Rapamycin (sirolimus)
Metformin and Rapamycin Rejuvenate Stem Cells in Mice Full Text +Metformin

Miscellaneous Molecules & Prescription Drugs
Assessing tolerability and physiological responses to 17α-estradiol administration in male rhesus macaques
*Neuroprotective effect of angiotensin II receptor blockers on the risk of incident Alzheimer’s disease: A nationwide population-based cohort study Full Text
Repurposing Canagliflozin to target brain aging Full Text
*Cardiovascular outcomes with SGLT2 inhibitors versus DPP4 inhibitors and GLP-1 receptor agonists in patients with heart failure with reduced and preserved ejection fraction Full Text

Other Areas of Interest (in alphabetical order)

Ageing Clocks & other biomarkers of ageing
*Centenarian clocks: epigenetic clocks for validating claims of exceptional longevity Full Text
*Association between biological aging and lung cancer risk: Cohort study and Mendelian randomization analysis Full Text
Retinal scans: A non-invasive, inexpensive method to track human aging Full Text

Blood Factors or other Heterochronic Transplantation
Young Blood Alters Gene Expression in Old Brain Cells Full Text
Young Astrocytic Mitochondria Attenuate the Elevated Level of CCL11 in the Aged Mice, Contributing to Cognitive Function Improvement Full Text
The profile of circulating extracellular vesicles depending on the age of the donor potentially drives the rejuvenation or senescence fate of hematopoietic stem cells Full Text
Role of age-related plasma in the diversity of gut bacteria

Epigenetics & Cellular Reprogramming
Epigenetic rejuvenation by partial reprogramming Full Text
The loss of epigenetic information: not only consequences but a cause of mammalian aging Full Text

Exosomes (small packets of information released by cells)
iPSC-sEVs alleviate microglia senescence to protect against ischemic stroke in aged mice Full Text
Exosomes from CD133+ human urine-derived stem cells combined adhesive hydrogel facilitate rotator cuff healing by mediating bone marrow mesenchymal stem cells Full Text
Urine-derived mesenchymal stem cells-derived exosomes enhances survival and proliferation of aging retinal ganglion cells Full Text

Genetics including CRISPR
Transcriptional activation of endogenous Oct4 via the CRISPR/dCas9 activator ameliorates Hutchinson-Gilford progeria syndrome in mice Full Text
Molecular and cognitive signatures of ageing partially restored through synthetic delivery of IL2 to the brain Full Text

Lifespan Lengthening Interventions
The longevity response to warm temperature is neurally controlled via the regulation of collagen genes Full Text
Lonafarnib improves cardiovascular function and survival in a mouse model of Hutchinson-Gilford progeria syndrome Full Text
Preparation and evaluation of ovalbumin-fucoidan nanoparticles for nicotinamide mononucleotide encapsulation with enhanced stability and anti-aging activity

Microbiome
*Mendelian randomization analyses reveal causal relationships between the human microbiome and longevity Full Text
Gut microbiota, an additional hallmark of human aging and neurodegeneration Full Text
*Six-Month Synbio® Administration Affects Nutritional and Inflammatory Parameters of Older Adults Included in the PROBIOSENIOR Project Full Text
*Positive Health Outcomes Associated with Live Microbe Intake from Foods, Including Fermented Foods, Assessed using the NHANES Database Full Text (Feb 2023)

Observational Studies
*Re-examination of successful agers with lower biological than chronological age still after a 20-year follow-up period Full Text
*Associations of body size with all-cause and cause-specific mortality in healthy older adults Full Text
*The relationship between midlife dyslipidemia and lifetime incidence of dementia: A systematic review and meta-analysis of cohort studies Full Text
*Effects of television viewing on brain structures and risk of dementia in the elderly: Longitudinal analyses Full Text

Opinion/Editorials/Theory
Ageing as a software design flaw Full Text
Whole organism aging: Parabiosis, inflammaging, epigenetics, and peripheral and central aging clocks. The ARS of aging Full Text
Beyond ‘Productive Aging’: An Argument for ‘Happy Aging’ Full Text

Other Ageing Biology
Study finds loss of Menin helps drive the aging process, and dietary supplement can reverse it in mice Full Text
Necroptosis inhibition counteracts neurodegeneration, memory decline, and key hallmarks of aging, promoting brain rejuvenation Full Text
Enhanced insulin-regulated phagocytic activities support extreme health span and longevity in multiple populations Full Text
Inhibiting DREAM for Enhanced DNA Damage Repair Full Text

Regenerative Medicine
3D bioprinted alginate-gelatin hydrogel patches containing cardiac spheroids recover heart function in a mouse model of myocardial infarction Full Text
Patient-specific cells generated from thymus organoids Full Text

Reproductive Health
Aging-Related Ovarian Failure and Infertility: Melatonin to the Rescue Full Text
Exploration of the Antioxidant Effect of Spermidine on the Ovary and Screening and Identification of Differentially Expressed Proteins Full Text
hUMSCs Restore Uterine Function by Inhibiting Endometrial Fibrosis via Regulation of the MMP-9/TIMP-1 Ratio in CDDP-Induced Injury Rats Full Text

Reviews
Cellular rejuvenation: molecular mechanisms and potential therapeutic interventions for diseases Full Text
Aging Hallmarks and the Role of Oxidative Stress Full Text
Potential of Polyphenols for Improving Sleep: A Preliminary Results from Review of Human Clinical Trials and Mechanistic Insights Full Text
Towards AI-driven longevity research: An overview Full Text

Senolytics/Senescent Cells
Effect of peripheral cellular senescence on brain aging and cognitive decline Full Text
Immunotherapeutic approach to reduce senescent cells and alleviate senescence-associated secretory phenotype in mice Full Text
Modeling of senescent cell dynamics predicts a late-life decrease in cancer incidence Full Text

Skin & Beauty
*Beauty from within: Improvement of skin health and appearance with Lycomato a tomato-derived oral supplement Full Text
*Tolerability and efficacy assessment of an oral collagen supplement for the improvement of biophysical and ultrasonographic parameters of skin in middle eastern consumers Full Text
*Oral intake of collagen peptide NS improves hydration, elasticity, desquamation, and wrinkling in human skin: a randomized, double-blinded, placebo-controlled study Full Text
*A Randomized Double-Blind, Placebo-Controlled Study to Evaluate the Anti-Skin-Aging Effect of LactoSporin – The Extracellular Metabolite from Bacillus coagulans (Weizmannia coagulans) MTCC 5856 in Healthy Female Volunteers Full Text

Telomeres
Instant Coffee Is Negatively Associated with Telomere Length: Finding from Observational and Mendelian Randomization Analyses of UK Biobank Full Text
*Very Low and High Levels of Vitamin D Are Associated with Shorter Leukocyte Telomere Length in 148,321 UK Biobank Participants Full Text
*Telomere length and brain imaging phenotypes in UK Biobank Full Text

Odds & Sods
*The medieval biological clock? Gendered reproductive aging in medieval western medicine Full Text
*Purpose in life promotes resilience to age-related brain burden in middle-aged adults Full Text
*The Effect of Cognitive Training with Neurofeedback on Cognitive Function in Healthy Adults: A Systematic Review and Meta-Analysis 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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