August 2024 Longevity Review

Hello again! I’m returning after a health related absence, so this review has taken a lot longer to get finished - trying now desperately to get back on track! I might combine the next two months into one so that I’ll have caught up.

August was highlighted by the results of the first human rapamycin study devoted to longevity; the synthesis of a novel autophagy activator which increased mouse lifespan; the improvement of aging in rats with MSC treatment; a review of combination treatments in mice; a look at the 11th Aging Research & Drug Discovery meeting; and for the Canadian content study, the discovery of a new DNA repair mechanism.

In the Supplemental Section, you’ll find in NMN, a couple of systematic reviews of human trials to date; in Other Supplements, how taking creatine can help with sleep on training days; in Combinations, how mTOR and SGLT-2 inhibitors could be synergistic; in Exosomes, how ultrasound preconditioned exosomes help with rotator cuff regeneration; in Genetics, how regenerative genes improves lifespan across the species barrier; in Observational Studies, how there are two distinct periods where rapid aging occurs; in Reproductive Health, how users of hormone therapy are biologically younger; and in Skin & Beauty, a review of Coenzyme Q10 for skiing aging. (To make these suggestions easier to find, I’ve marked them with ***)

Donate to the Canadian Longevity Association to help bring about a future where we don’t die of aging related diseases!

Please also follow, or join us on social media:

Twitter/X (I also have a personal account with more frequent longevity updates)

Facebook Instagram LinkedIn Meetup

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

Discord for longevity related chats and the place to have all your longevity related questions answered.

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.
Finally, 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.

August 2024 Highlights:

I’m delighted to bring you the results of the very first rapamycin trial designed from the outset to investigate longevity. I’m especially excited as I was involved in the crowdfunding campaign, helping to write the campaign page and being one of the donors. The trial lasted for 48 weeks and featured 114 participants which took either 5mg, 10mg of rapamycin or a placebo once a week.

Although aimed at longevity as the target, this trial was still primarily a safety trial, hoping to get as many learnings as possible for subsequent larger trials. Unfortunately, the biggest learning was that the compounded form of rapamycin used was only 28% as bioavailable as the generic version, so that the 5mg and 10mg doses translated to roughly 1.4mg and 2.9mg respectively. The authors only found this out once the trial was underway and is the subject of the first paper shown below.

The most important result was that weekly low dose rapamycin was safe to take for a large number of people with minimal side effects, in fact, any minor side effects were similar to placebo. As for changes caused by rapamycin, “Lean tissue mass and self-reported pain improved significantly for women using 10mg rapamycin. Trends of improvement in bone mineral density were observed in males using 10mg rapamycin, but no other significant effects were observed.”

Although I had hoped that there would be more significant effects, it is not particularly surprising considering the reduced doses, and fortunately there were still effects at those doses. The authors will take the learnings and apply them to subsequent larger and longer lasting trials. In addition, this is only the first paper, with other parameters still to be reported on. Note: this study is still a pre-print, so it has yet to be peer reviewed.
*The bioavailability of compounded and generic rapamycin in normative aging individuals: A retrospective study and review with clinical implications Full Text
*Safety and efficacy of rapamycin on healthspan metrics after one year: PEARL Trial Results Full Text

Here, researchers synthesised a novel autophagy (a recycling mechanism in our cells) activator, CXM102, which rejuvenated bone marrow stem cells. This resulted in increased bone growth, and less bone loss in middle aged mice. In addition, inflammation and organ fibrosis was decreased. Most noteworthy, CXM102 treatment led to increased lifespan, which surpassed that of rapamycin, which acted as a positive control (though the number of animals was so small that it could just be statistical noise). Very interested to see larger lifespan studies carried out on this new molecule.
Rejuvenation of BMSCs senescence by pharmacological enhancement of TFEB-mediated autophagy alleviates aged-related bone loss and extends lifespan in middle aged mice Full Text

In this study researchers thoroughly tested the anti-aging effects of human derived umbilical Mesenchymal Stromal Cells (MSCs), a form of stem cells, in older rats. The MSCs turned out to reduce oxidative stress, repair tissue, regulate metabolism and improve immune functions across multiple organs. They also altered the microbiota towards a more youthful state. Altogether showing that MSCs “concurrently regulate multiple aging processes and improve a range of aging phenotypes”, “thus presenting a promising anti-aging therapeutic approach.”
MSC Treatment Improves Age-Related Phenotypes in Rats Full Text

I normally don’t include reviews in the Highlights section, but when that review is of all the combination studies done in mice for longevity, I make an exception! If you’ve read these reviews before, you’ll know that I continually emphasise that effective longevity treatments are going to require multiple avenues of attack as aging is such a multifaceted problem.

This review is a great resource, as it lists each of the interventions, gives the primary hallmark of aging it targets as well as giving the percentage of lifespan increase. Well worth your perusal.
Combining Treatments Against Multiple Hallmarks of Aging Full Text

Finishing off with another longevity conference, this time with the biggest and most important of them all - the Aging Research and Drug Discovery meeting (ARDD), held in Copenhagen at the end of every summer. This year was the biggest ever, with more than 160 talks, and you can read about in this write up by Arkadi Mazin of Lifespan.io:
For the 11th Year in Copenhagen: Highlights from ARDD 2024 ARDD Website
In addition, most of the talks are recorded and are uploaded to the meeting’s YouTube channel. ARDD YouTube Channel

Canadian Content Study

From Western University, first author Robert Szabla and his group have discovered a new DNA repair mechanism in the bacterium Deinococcus Radiodurans, which is one of the hardiest organisms, being able to withstand huge amounts of radiation. The mechanism consists of a single protein, DdrC, which scans DNA, and then snaps shut like a mousetrap when it detects damage, alerting the cell to then fix that damage. Equally excitingly, they were able to transfer this protein to another single celled organism, making it much more resistant to DNA damage.

This could in theory be applied to human cells as well, which is a direction the research team will be moving in, as shared to me by Robert that “we will be exploring whether exogenous DdrC can improve DNA damage resistance in human cells”. Watch this space!
Newly discovered protein stops DNA damage Full Text Brief YouTube Video

Further Canadian content is indicated by CAN

Supplemental Section

Lifestyle
*A healthy lifestyle may counteract diabetes-associated brain aging Full Text
*Association between Life's Essential 8 and cognitive function among older adults in the United States Full Text

Fasting/Dietary Restriction – certainly the cheapest & also one of the most effective anti-ageing interventions currently available.
Spermidine is essential for fasting-mediated autophagy and longevity Full Text
Fasting and calorie restriction modulate age-associated immunosenescence and inflammaging Full Text

Diet – let food be thy medicine…
*Anti-Inflammatory Diets Mitigate Risk of Dementia Full Text
*Red and processed meat consumption associated with higher type 2 diabetes risk, study of two million people finds Full Text
*Dietary trajectories over 21 years and frailty in Norwegian older adults: the Tromsø Study 1994–2016 Full Text
*Plant but not animal sourced nitrate intake is associated with lower dementia-related mortality in the Australian Diabetes, Obesity, and Lifestyle Study Full Text
*Alcohol Consumption Patterns and Mortality Among Older Adults With Health-Related or Socioeconomic Risk Factors Full Text

Exercise – if you could bottle the benefits of exercise, it would be the biggest blockbuster drug of all time.
*Associations Between Professional Sports and Longevity Full Text
*Weekend-Oriented Physical Activity Superior for Brain Health Abstract

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.
*The effect of astaxanthin after varicocele surgery on antioxidant status and semen quality in infertile men: A triple-blind randomized clinical trial Full Text
*Exploring the Impact of Astaxanthin Supplementation in Conjunction with a 12-Week CrossFit Training Regimen on Selected Adipo-Myokines Levels in Obese Males 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: A Golden Approach to Healthy Aging: A Systematic Review of the Evidence Full Text
Curcumin and Cognitive Function: A Systematic Review of the Effects of Curcumin on Adults With and Without Neurocognitive Disorders Full Text

Ketones
*Daily consumption of ketone ester, bis-octanoyl ®-1,3-butanediol, is safe and tolerable in healthy older adults in a randomized, parallel arm, double-blind, placebo-controlled, pilot study Full Text
A Ketosis-Related Compound Alleviates Arthritis in Rats Full Text

Nicotinamide MonoNucleotide (NMN)
*Efficacy of oral nicotinamide mononucleotide supplementation on glucose and lipid metabolism for adults: a systematic review with meta-analysis on randomized controlled trials Full Text***
*Improved Physical Performance Parameters in Patients Taking Nicotinamide Mononucleotide (NMN): A Systematic Review of Randomized Control Trials Full Text***

Nicotinamide Riboside (NR)
Nicotinamide riboside modulates the reactive species interactome, bioenergetic status and proteomic landscape in a brain-region-specific manner Full Text

Pterostilbene
Effects of Pterostilbene on Cardiovascular Health and Disease Full Text

Resveratrol
*Oral resveratrol in adults with knee osteoarthritis: A randomized placebo-controlled trial (ARTHROL) Full Text

Spermidine
A surge in endogenous spermidine is essential for rapamycin-induced autophagy and longevity Full Text
*Non-Linear Association of Dietary Polyamines with the Risk of Incident Dementia: Results from Population-Based Cohort of the UK Biobank Full Text

Other available supplements or natural substances (in alphabetical order)
*Vitamin B12 status and skeletal muscle function among elderly: A literature review and pilot study on the effect of oral vitamin B12 supplementation in improving muscle function Full Text
The impact of carnosine on biological ageing – A geroscience approach Full Text
*Creatine Improves Total Sleep Duration Following Resistance Training Days versus Non-Resistance Training Days among Naturally Menstruating Females Full Text***
*Comparison of functional performance outcomes between oral patented crystalline glucosamine sulfate and platelet-rich plasma among knee osteoarthritis patients: a propensity score matching analysis Full Text
Effects of Ginger (Zingiber officinale) on the Hallmarks of Aging Full Text
*ω-3 PUFA for Secondary Prevention of White Matter Lesions and Neuronal Integrity Breakdown in Older Adults Full Text
Omega-3 PUFAs slow organ aging through promoting energy metabolism Full Text
Rosemary extract activates oligodendrogenesis genes in mouse brain and improves learning and memory ability Full Text
Mitigation of aging-related plasticity decline through taurine supplementation and environmental enrichment Full Text
Bidirectional Effect of Long-Term Δ9-Tetrahydrocannabinol Treatment on mTOR Activity and Metabolome Full Text

Combinations
mTOR and SGLT-2 Inhibitors Impact Age-Related Processes Full Text***
*A Randomised, Double-Blind, Placebo-Controlled, Cross-Over Clinical Trial to Evaluate the Biological Effects and Safety of a Polyphenol Supplement on Healthy Ageing Full Text
Synergistic anti-aging effect of Dendrobium officinale polysaccharide and spermidine: A metabolomics analysis focusing on the regulation of lipid, nucleotide and energy metabolism
*Functional and metabolic effects of omega-3 polyunsaturated fatty acid supplementation and the role of β-hydroxy-β-methylbutyrate addition in chronic obstructive pulmonary disease: A randomized clinical trial Full Text

Prescription Supplements

Metformin
Metformin: From diabetes to cancer to prolongation of life Full Text

Rapamycin (sirolimus)
Calorie restriction and rapamycin distinctly mitigate aging-associated protein phosphorylation changes in mouse muscles Full Text
Rapamycin Attenuates H2O2-Induced Oxidative Stress-Related Senescence in Human Skin Fibroblasts

Miscellaneous Molecules & Prescription Drugs
GDF11 protects against mitochondrial-dysfunction-dependent NLRP3 inflammasome activation to attenuate osteoarthritis Full Text
*Comparative renal outcomes of matched cohorts of patients with type 2 diabetes receiving SGLT2 inhibitors or GLP-1 receptor agonists under routine care Full Text

Other Areas of Interest (in alphabetical order)

Ageing Clocks & other biomarkers of ageing
*Proteomic aging clock predicts mortality and risk of common age-related diseases in diverse populations Full Tex
New Epigenetic Clock Built on Lurking DNA Fragments Full Text
*A systematic review of phenotypic and epigenetic clocks used for aging and mortality quantification in humans Full Text

Blood Factors or other Heterochronic Transplantation
Aging insights from heterochronic parabiosis models Full Text

Epigenetics & Cellular Reprogramming
Some Cells Age Much Faster Than Others Full Text

Exosomes (small packets of information released by cells)
Engineered exosome therapeutics for neurodegenerative diseases Full Text
Exosomes derived from bone marrow mesenchymal stem cell preconditioned by low-intensity pulsed ultrasound stimulation promote bone–tendon interface fibrocartilage regeneration and ameliorate rotator cuff fatty infiltration Full Text***
Exploring senescence as a modifier of β cell extracellular vesicles in type 1 diabetes Full Text CAN

Genetics including CRISPR
Highly regenerative species-specific genes improve age-associated features in the adult Drosophila midgut Full Text***

Lifespan Lengthening Interventions
Heat-killed probiotic Levilactobacillus brevis MKAK9 and its exopolysaccharide promote longevity by modulating aging hallmarks and enhancing immune responses in Caenorhabditis elegans Full Text
Newly discovered gene may influence longevity Full Text
Characterization of effects of mTOR inhibitors on aging in C. elegans Full Text

Microbiome
Association between Accelerated Biological Aging, Diet, and Gut Microbiome Full Text
The Role of Akkermansia muciniphila on Improving Gut and Metabolic Health Modulation: A Meta-Analysis of Preclinical Mouse Model Studies Full Text

Observational Studies
*Association between weight change and serum anti-aging protein α-Klotho: a cross-sectional study in middle-aged and older adults Full Text
*Nonlinear dynamics of multi-omics profiles during human aging Full Text***
*Individual socioeconomic status, neighborhood disadvantage, and cognitive aging: A longitudinal analysis of the CLSA Full Text CAN
*The association between trajectories of marital status and successful aging varies by sex: Findings from the Canadian Longitudinal Study on Aging (CLSA) Full Text CAN

Opinion/Editorials/Theory
Inflated expectations: the strange craze for translational research on aging: Given existing confusion about the basic science of aging, why the high optimism in the private sector about the prospects of developing anti-aging treatments? Full Text
Enhanced cellular longevity arising from environmental fluctuations Full Text

Other Ageing Biology
Cleaning up the aging brain: Scientists restore brain's trash disposal system Cleaning up the aging brain Abstract
*Inflammation May Drive Fat Distribution in Older People Full Text
Why Bone Destruction Is Accelerated with Aging Full Text

Reproductive Health
*Hormone Therapy and Biological Aging in Postmenopausal Women Full Text***
A scoping review regarding reproductive capacity modulation based on alpha-ketoglutarate supplementation Full Text
*Effect of astaxanthin supplementation on female fertility and reproductive outcomes: a systematic review and meta-analysis of clinical and animal studies Full Text

Reviews
Precision epigenetic editing: Technological advances, enduring challenges, and therapeutic applications Full Text
Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies Full Text
Anti-ageing interventions for the treatment of cardiovascular disease Full Text
Advances in targeted therapies for age-related osteoarthritis: A comprehensive review of current research Full Text

Senolytics/Senescent Cells
Senolytic intervention improves cognition, metabolism, and adiposity in female APPNL−F/NL−F mice Full Text
Glutaminase-1 inhibition alleviates senescence of Wharton’s jelly-derived mesenchymal stem cells via senolysis Full Text
Intermittent clearance of p21-highly-expressing cells extends lifespan and confers sustained benefits to health and physical function

Skin & Beauty
The Role of Coenzyme Q10 in Skin Aging and Opportunities for Topical Intervention: A Review Full Text***
*Influence of collagen peptide supplementation on visible signs of skin and nail health and -aging in an East Asian population Full Text
*Cosmeceuticals: A Review of Clinical Studies Claiming to Contain Specific, Well-Characterized Strains of Probiotics or Postbiotics Full Text
How Supplement Formulas, Including NOVOS, Affect Skin Aging Full Text

Telomeres
The Impact of the Mediterranean Diet on Telomere Biology: Implications for Disease Management—A Narrative Review Full Text
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
***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.*
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------