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September & October 2024 Longevity Review Part 1
supplements exosomes dietary restriction rapamycin lifestyle exercise nmn nad
In a bid to finally catch up with these Longevity Reviews, I took the decision to combine the results for September and October. This led to a fair amount of hand wringing as I sought to include only the biggest and most important studies for those two months, but my final selection for the Highlights Sections sees us taking a look at the most comprehensive dietary restriction study in mice to date; how the rat lifespan record might have been broken with exosome treatment; how an inhibitor of hyaluronan synthesis increases lifespan in mice; how exercise intensity is more important than volume for mortality reduction and, in the Canadian Content Study, how a protector of neurons plays a greater role in lifespan.
As a result of this merger, the supplemental section is bigger than normal. I tried to condense it as much as possible, but there were just too many studies that had to be included. Therefore, as a brief taster, you’ll find in Lifestyle the link between cardiovascular health and cancer mortality; in Fasting, how eating late affects blood glucose; in Diet, how dietary diversity affects aging; in other Supplements, reviews of Hesperetin & NAC; in Metformin, how it slows down aging in non-human primates; in Epigenetics, reprogramming senescent cells extends mouse lifespan; in Genetics, the use of CRISPR to find new ways to rejuvenate brain stem cells; in Opinion, some new theories on aging; in Reproductive Health, how genistein can help with menopause; and finally, in Telomeres, how astragalus increased telomere length in a human trial. (To make these suggestions easier to find, I’ve marked them with ***)
NOTE: The original post was too long, so I have split the Supplemental Section in two to accomodate the limit.
Canadian Longevity Association News
The big news over the last two months is that we’ve opened up an online shop!
That’s right, just in time for Christmas, you have all your shopping needs sorted! LOL
But seriously, you can now help fund the CLA’s activities, while sporting our logo on a wide and growing range of apparel. Take a look at our shop and if there is anything missing that you’d like to purchase, then drop us a line and we’ll happily and quickly add it.
Link to the CLA’s Online Store
Please also follow, or join us on social media:
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Previous newsletters can be found in the CLA Facebook Group, and also my Patreon account, which includes bonus material for supporters if you want to buy us a coffee.
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Sep/Oct 2024 Highlights:
In the largest comparative study of different forms of dietary restriction in female mice, scientists from CALICO discovered some really interesting and puzzling results. They studied 20% and 40% caloric restriction, as well as 1 and 2 days a week fasting. The median and maximum respectively for each compared to the control were as follows: 20CR: 18% & 22%; 40CR: 36% & 38%; 1DF: 12% & 6%; 2DF: 11% & 15%.
The 40% caloric restriction mice were clearly the winners, but changes to their immune system might make them more susceptible to infection. Another big puzzle was that lower weight and fat was better in early life, but then reversed in late life. As the authors put it, “DR extends lifespan while decreasing body weight and fat mass, yet preserving body weight and fat mass is associated with longer lifespan. This paradox is a recurrent theme in this study.”
This is a really in depth and readable study, and I do recommend that you take a look at it.
Study probes how eating less can extend lifespan Full Text
A research group who have been following since they started out, and who I have covered several times in these highlights, have released their latest results. E5, a young blood plasma fraction mainly consisting of exosomes, was previously shown to reduce the epigenetic age and improve various biomarkers in rats. This new study, along with once again showing improved biomarkers and grip strength, takes it further by including lifespan. And, the result of that was that the median lifespan improved by 9.7% over controls. More tantalizingly, one of the rats potentially broke the rat lifespan record for this strain, dying at the age of 48 months, which was a 21.7% increase over the longest lived control rat!
This was a very small study, with only 8 rats in each group, however I believe this to have great potential. Especially as they used young plasma from a different species, in case pigs, which means that if it were to work in humans, there would not be an issue of supply or ethical considerations. In correspondence with the researchers, I was told that they have now moved on to larger animals, specifically beagle dogs, with so far positive results, including a 50% reduction in IL-6, which they intend to publish in the coming year. This time, to further prove the cross species applicability, they have used young blood plasma from horses. In addition, they plan to test it on old cats with chronic kidney disease next year as well. If these studies are successful, the next step will be into humans. Needless to say, my fingers are crossed as I impatiently await the results!
Exosomes Break Rat Lifespan Record Full Text
In this study, it was found that an inhibitor of hyaluronan (hyaluronic acid) synthesis, 4-MU, increased the average and maximum lifespan of male mice by more than 20%. It seemed to do this by reducing blood glucose and increasing insulin sensitivity. Interestingly, the mice weighed less despite eating the same amount of food. This was a very small study, but this molecule is already in human trials, where it has recently passed phase 2a for pulmonary hypertension. I will be watching out for this molecule in the future.
Hymecromone Promotes Longevity and Insulin Sensitivity in Mice Full Text
Taking data from 7.5K US adults who wore actigraphs to measure their physical activity and were followed for seven years to assess mortality risk, it was unsurprisingly found that a greater volume and intensity of exercise was associated with reduced risk of death. However, it appears that intensity is more important than volume. Also longer continuous bouts of exercise were better than the same amount of exercise broken down into smaller chunks. There is a really nice infographic at the beginning of the article which does a good job summarizing these findings, and is worth checking out.
*Exercise Intensity, Duration, and Amount All Matter Full Text
Canadian Content Study
From McMaster University, researchers led by Bhagwati Gupta, have discovered how MANF, a protein which helps to protect neurons, plays a greater role in cell survival by regulating protein folding and clumping, as well as autophagy, the recycling system in cells. Working with c.elegans worms, those which lacked MANF had shorter survival times, while those which had more of it had 21% greater lifespan, and survived stress better. MANF is found in all animals, including us, and could play a role in healthy longevity.
From correspondence with Bhagwati, he said their current research “explores the proteins that interact with MANF to mediate its function and how secreted MANF affects different tissues and neuronal cells. We are also investigating the dynamics of MANF expression to better understand its role in cellular processes.” We wish them luck!
Protein shakeup: Researchers uncover new function of a protein that may unlock age-related illnesses Abstract Preprint Full Text
Further Canadian content is indicated by CAN
Supplemental Section
Lifestyle
*Cardiovascular health and cancer mortality: evidence from US NHANES and UK Biobank cohort studies Full Text***
*Phenotypic age mediates effects of Life's Essential 8 on reduced mortality risk in US adults Full Text
*Optimal lifestyle patterns for delaying ageing and reducing all-cause mortality: insights from the UK Biobank Full Text
*Tree-based analysis of longevity predictors and their ten-year changes: a 35-Year mortality follow-up Full Text
*Mediterranean Diet-Based Sustainable Healthy Diet and Multicomponent Training Combined Intervention Effect on Body Composition, Anthropometry, and Physical Fitness in Healthy Aging 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.
*Associations of daily eating frequency and nighttime fasting duration with biological aging in Full Text***
*Late eating is associated with poor glucose tolerance, independent of body weight, fat mass, energy intake and diet composition in prediabetes or early onset type 2 diabetes Full Text
*The Effects of Time-Restricted Eating on Fat Loss in Adults with Overweight and Obese Depend upon the Eating Window and Intervention Strategies: A Systematic Review and Meta-Analysis Full Text
Diet – let food be thy medicine…
*Association between plant and animal protein and biological aging: findings from the UK Biobank Full Text
*Intake of vegetables and fruits at midlife and the risk of physical frailty in later life Full Text
*A reduced carbohydrate diet improves glycemic regulation in hyperglycemic older people in a retirement home: The SAGE study CAN
*Dietary Diversity Is Associated With Delayed Aging Full Text***
Exercise – if you could bottle the benefits of exercise, it would be the biggest blockbuster drug of all time.
*Optimal dose and type of exercise to improve cognitive function in patients with mild cognitive impairment: a systematic review and network meta-analysis of RCTs Full Text
*Hydrolyzed collagen supplementation prior to resistance exercise augments collagen synthesis in a dose-response manner in resistance-trained, middle-aged men
*Does Taking a Break Matter—Adaptations in Muscle Strength and Size Between Continuous and Periodic Resistance Training 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 assisted reproductive technology outcomes in poor ovarian responders through alleviating oxidative stress, inflammation, and apoptosis: a randomized clinical trial Full Text
*Astaxanthin compound nutrient improved insulin resistance, hormone levels, embryo quality and pregnancy outcomes in polycystic ovary syndrome patients undergoing in vitro fertilization/intracytoplasmic sperm injection 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 effect of curcumin supplementation on glycemic indices in adults: A meta-analysis of meta-analyses
*The effect of curcumin supplementation on endothelial function and blood pressure in patients with metabolic disorders: A meta-analysis of meta-analyses
*Curcumin extract improves beta cell functions in obese patients with type 2 diabetes: a randomized controlled trial Full Text
Fisetin
Fisetin as a Senotherapeutic Agent: Evidence and Perspectives for Age-Related Diseases Full Text
Melatonin
Dysfunctional mitochondria in age-related neurodegeneration: Utility of melatonin as an antioxidant treatment Full Text
Unlocking the health benefits of melatonin supplementation: A promising preventative and therapeutic strategy Full Text
Nicotinamide MonoNucleotide (NMN)
Nicotinamide mononucleotide supplementation rescues mitochondrial and energy metabolism functions and ameliorates inflammatory states in the ovaries of aging mice Full Text
Research advances in the function and anti-aging effects of nicotinamide mononucleotide Full Text
*The versatile multi-functional substance NMN: its unique characteristics, metabolic properties, pharmacodynamic effects, clinical trials, and diverse applications Full Text
Nicotinamide Riboside (NR)
NAD+ depletion is central to placental dysfunction in an inflammatory subclass of preeclampsia Full Text CAN
Pterostilbene
From Nature to Treatment: The Impact of Pterostilbene on Mitigating Retinal Ischemia–Reperfusion Damage by Reducing Oxidative Stress, Inflammation, and Apoptosis Full Text
Exploration of Nutraceutical Potentials of Isorhapontigenin, Oxyresveratrol and Pterostilbene: A Metabolomic Approach Full Text
Resveratrol
Resveratrol as a potential therapeutic agent for sarcopenic obesity: Insights from in vivoperiments Full Text
Resveratrol delays the progression of diabetic nephropathy through multiple pathways: A dose–response meta-analysis based on animal models Full Text
The role and current research status of resveratrol in the treatment of osteoarthritis and its mechanisms: a narrative review Full Text
Spermidine
The longevity factor spermidine is part of a highly heritable complex erythrocyte phenotype associated with longevity Full Text
Other available supplements or natural substances (in alphabetical order)
*Efficacy of Berberis vulgaris and Berberis integerrima on glycemic indices and weight profile in type 2 diabetic patients: A systematic review and meta-analysis of randomized controlled trials Full Text
*Blueberry Extract Aids Cognition in People With Inflammation Full Text
The impact of cysteine on lifespan in three model organisms: A systematic review and meta-analysis Full Text
Comprehensive review of Hesperetin: Advancements in pharmacokinetics, pharmacological effects, and novel formulations Full Text***
*N-acetylcysteine Clinical Applications Full Text***
*Dose–response relationship of dietary Omega-3 fatty acids on slowing phenotypic age acceleration: a cross-sectional study Full Text
Royal jelly a promising therapeutic intervention and functional food supplement: A systematic review Full Text
Combinations
Plant extracts and omega-3 improve short-term memory and modulate the microbiota-gut-brain axis in D-Galactose model mice Full Text
Plant extracts and omega-3 supplementation modulate hippocampal oxylipin profile in response to LPS-induced neuroinflammation Full Text
The Combined Effect of Green Tea, Saffron, Resveratrol, and Citicoline against Neurodegeneration Induced by Oxidative Stress in an In Vitro Model of Cognitive Decline Full Text
Prescription Supplements
Metformin
The brain aged more slowly in monkeys given a cheap diabetes drug
Metformin Slows Aging in Non-Human Primates Abstract ***
*Metformin Exhibits Anti-Inflammatory Effects by Regulating microRNA-451/CXCL16 and B Cell Leukemia/Lymphoma 2 in Patients With Osteoarthritis Full Text
Metformin: Beyond Type 2 Diabetes Mellitus Full Text
Rapamycin (sirolimus)
Calorie restriction and rapamycin distinctly restore non-canonical ORF translation in the muscles of aging mice Full Text
Rapamycin Treatment Reduces Brain Pericyte Constriction in Ischemic Stroke Full Text
*A single-center, double-blind, randomized, placebo-controlled, two-arm study to evaluate the safety and efficacy of once-weekly sirolimus (rapamycin) on muscle strength and endurance in older adults following a 13-week exercise program Full Text
Miscellaneous Molecules & Prescription Drugs
*Effect of frailty on effectiveness and safety of GLP-1 receptor agonists versus SGLT2 inhibitors in people with type 2 diabetes in Taiwan: a retrospective, nationwide, longitudinal study Full Text
Expanding access to weight-loss drugs could save thousands of lives a year Full Text
*Association between statin usage and mortality outcomes in aging U.S. cancer survivors: a nationwide cohort study Full Text
*Association between prescription drugs and all-cause mortality risk in the UK population Full Text
Novel Molecules
Blocking a Dopamine Receptor May Improve Memory Full Text
NX210c drug candidate peptide strengthens mouse and human blood-brain barriers 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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