March 2025 Longevity Review

As the flowers are finally starting to bloom in my garden, we will take a look at an intriguing study which uses ultrasound to reverse cellular senescence and increase mouse lifespan; two studies on reducing lower back pain, the first using epigenetic reprogramming, while the second is a Canadian study using senolytics; and, a fascinating study where an induced torpor like state (akin to hibernation) improves healthspan.

In the Supplemental Section, you’ll find in Lifestyle a couple of studies on the importance of sleep for mortality and stroke risk; in Diet, a Canadian study on optimal dietary patterns for healthy aging; in Exercise, how any form of exercise can boost brain function; in Other Supplements, how citrulline can help with aging; in Combinations, the results of human trials on two commercial supplement stacks; and, in Blood Factors, how giving blood could give yourself health benefits. Plus of course much more! (To make these suggestions easier to find, I’ve marked them with ***)

PUBLISHING NOTE: It is with a heavy heart that I have to let you know that these newsletters will be switching to bi-monthly, or every second month from now on. I’ve been producing them monthly since the beginning of 2019, with the accompanying videos starting in 2022, and have always put my soul into them. They marked my first foray into longevity advocacy and ultimately led to the founding of the CLA. However, they take an immense amount of time to put together, and in the past couple of years have been getting in the way of my CLA work. Despite various attempts to rearrange my schedule and to be more productive, it has proven to be impossible to drastically reduce the amount of time devoted to them without taking this step. But, it should result in much faster progress with the CLA. I hope for your understanding.

Canadian Longevity Association News

Apart from having done our taxes for 2024, getting corporate credit and debit cards, and starting to post on Bluesky, the major news is that the CLA is finally getting representation on the west coast, with the onboarding of our latest volunteer - a warm welcome to Stephen! The CLA is looking to get representatives in every province and territory, as most of healthcare is implemented at the provincial level and a large part of our advocacy efforts must also be tailored to that level. Get in touch if you would be interested in becoming a CLA representative where you live.

Link to the CLA’s Online Store

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 TikTok Bluesky

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.

March 2025 Highlights:

This study really caught my attention as it suggests that low frequency ultrasound could be a longevity treatment of the future. In this study, researchers were able to reverse cellular senescence and increase the lifespan of mice, as well as improving their appearance and movement. Animals were placed in a water bath and treated with ultrasound at a specific frequency for 30 minutes at varying doses and schedules. Animals given lower doses (every second or third day) saw the biggest improvement in lifespan. You can watch brief videos of the differences between the treated and control mice inside the paper or in my review. Looking ahead, if these results are replicated and considering how many millions of people worldwide have safely had ultrasounds, I can imagine this swiftly moving into human studies.
Rejuvenation of Senescent Cells, In Vitro and In Vivo, by Low-Frequency Ultrasound Full Text
CLA Video Review

Additional study from March showing benefits of ultrasound for senescence:
Low-intensity pulsed ultrasound inhibits chondrocyte senescence by inhibiting PI3K/AKT/mTOR signaling Full Text

Lower back pain is one of the most common chronic conditions of aging, affecting more than 80% of us at some point in our lives. It is mainly caused by intervertebral disk degeneration (IVDD) and is a leading cause of disability and loss of quality of life. Although symptoms can be reduced, there is no cure. However, that could change in the future as shown by the first of two highlighted studies into reducing lower back pain. Here, researchers used epigenetic reprogramming to reduce markers of senescence and reverse degeneration in rats, as well as reduce certain measures of pain. This is still very early days, but this is another study highlighting the potential power epigenetic reprogramming.
Reprogramming Epigenetics to Fight Back Pain Full Text CLA Video Review

In this fascinating study, researchers were able to induce a torpor-like state, which is similar to hibernation, in mice. This led to a decreased metabolic rate and lowered body temperature, which resulted in a slowing down of epigenetic aging across multiple tissues and improved healthspan. It will be interesting to see if these results end up leading to any future treatments.
A torpor-like state in mice slows blood epigenetic aging and prolongs healthspan Full Text
No video review for this one - sorry!

Canadian Content Study

Coming out of the lab of Lisbet Haglund of McGill University, our second highlighted study for reducing lower back pain uses the senolytics o-vanillin and RG-7112 to remove senescent cells from the spine and improve lower back pain in a mouse model of early IVDD. The combination of the two senolytics worked better than either alone.

Haglund’s lab is currently working on a study to see if the same senolytics can prevent back pain from occurring in the first place, as well as prevent bone loss in a separate study in wild-type mice. They are also optimising o-vanillin’s pharmacokinetic properties. Hopefully all this work will eventually result in some human clinical trials!
Senolytics Decrease Low Back Pain in Mice Full Text CLA Video Review
Further Canadian content is indicated by CAN

Supplemental Section

Lifestyle
*Healthy lifestyle habits, educational attainment, and the risk of 45 age-related health and mortality outcomes in the UK: A prospective cohort study Full Text
*Imbalanced sleep increases mortality risk by 14–34%: a meta-analysis Full Text***
*Inadequate sleep increases stroke risk: evidence from a comprehensive meta-analysis of incidence and mortality Full Text***

Fasting/Dietary Restriction
Intermittent fasting boosts sexual behavior by limiting the central availability of tryptophan and serotonin Full Text
*Relationship between dietary energy and macronutrient intake at dinner versus breakfast and biological aging and premature mortality: Assessment of 2003–2014 National Health and Nutrition Examination Survey participants
Time restricted feeding with or without ketosis influences metabolism-related gene expression in a tissue-specific manner in aged rats Full Text

Diet
*Huge Diet Study: More Butter, More Problems Full Text
*Dietary Patterns Associated With Healthy Aging Full Text*** CAN
*Almond snacking modulates gut microbiome and metabolome in association with improved cardiometabolic and inflammatory markers Full Text
*The effects of wine consumption and lipid profile: A systematic review and meta-analysis of clinical trials Full Text

Exercise
*Age-Related Differences in Adaptation of Lean Body Mass, Muscle Strength, and Performance Following 6 Weeks of Blood Flow Restriction Training in Young and Older Adults Full Text CAN
*Exercise of any kind boosts brainpower at any age Full Text***
*Sex-specific effects of intensity and dose of physical activity on BOLD-fMRI cerebrovascular reactivity and cerebral pulsatility Full Text CAN
*Impact of combined high-intensity bodyweight interval training and breathing exercise on cardiometabolic health in normal-weight middle-aged adults with hypertension Full Text

Non-prescription Supplements (in alphabetical order)

Curcumin
*An Umbrella Review of Systematic Reviews and Meta-analyses of Randomized Controlled Trials Investigating the Effect of Curcumin Supplementation on Lipid Profiles Full Text
*Impacts of Curcumin Supplementation on Cardiometabolic Risk Factors in Patients With Polycystic Ovary Syndrome: A Systematic Review and Dose−Response Analysis Full Text
Impact of curcumin on gut microbiome Full Text

Fisetin
Combination Therapy of Losartan and Fisetin Reduces Senescence and Enhances Osteogenesis in Human Bone Marrow–Derived Mesenchymal Stem Cells Full Text

Resveratrol
*Resveratrol Upregulates Antioxidant Factors Expression and Downmodulates Interferon-Inducible Antiviral Factors in Aging Full Text
*Microbiota-derived resveratrol metabolites: New biomarkers of red wine consumption are inversely associated with inflammation in a longitudinal study of a Mediterranean population Full Text
*Impact of Resveratrol Supplementation on Human Sirt1: A GRADE-Assessed Systematic Review and Dose-Response Meta-Analysis of Randomized Controlled Trials (RCTs) Full Text

Other available supplements or natural substances (in alphabetical order)
Carotenoids for Antiaging: Nutraceutical, Pharmaceutical, and Cosmeceutical Applications Full Text
Citrulline regulates macrophage metabolism and inflammation to counter aging in mice Full Text***
*Unveiling the geroprotective potential of Monarda didyma L.: insights from in vitro studies and a randomized clinical trial on slowing biological aging and improving quality of life Full Text
*Nicotinic acid increases adipose tissue dietary fatty acid trapping and reduces postprandial hepatic and cardiac fatty acid uptake in prediabetes Full Text CAN
*Effect of 12-week dietary nitrate supplementation on carotid arterial stiffness in postmenopausal females Full Text
*BEETter AGING: Short-Term Dietary Nitrate Supplementation Enhances Muscle Contractile Properties in Older But Not in Young Adult
*Increasing nitric oxide availability via ingestion of nitrate-rich beetroot juice improves vascular responsiveness in individuals with Alzheimer’s Disease. Full Text
*Systemic immune inflammation mediates the association of serum omega-3 and omega-6 polyunsaturated fatty acids with biological aging: a national population-based study Full Text
*Elevated urinary phytoestrogens are associated with delayed biological aging: a cross-sectional analysis of NHANES data Full Text

Combinations
*Effects of vitamin D3, omega-3 fatty acids and a simple home exercise program on change in physical activity among generally healthy and active older adults: The 3-year DO-HEALTH trial Full Text
Assessment of the Capability of Mesenchymal Stem Cells and/or Pyrroloquinoline Quinone in Compensating the Age-Related Dysfunctions of AMP-Activated Protein Kinase Pathway in Wistar Rats
*The efficacy of Sarcomeal® oral supplementation plus vitamin D3 on muscle parameters, metabolic factors, and quality of life in diabetic sarcopenia: a randomized controlled clinical trial Full Text
*Effects of a natural ingredients-based intervention targeting the hallmarks of aging on epigenetic clocks, physical function, and body composition: a single-arm clinical trial Full Text***
*Enhancement of NK Cell Cytotoxic Activity and Immunoregulatory Effects of a Natural Product Supplement Across a Wide Age Span: A 30-Day In Vivo Human Study Full Text***
Nicotinamide mononucleotide combined with PJ-34 protects microglial cells from lipopolysaccharide-induced mitochondrial impairment through NMNAT3-PARP1 axis Full Text

Prescription Supplements

Metformin
*Metformin and physical performance in older people with probable sarcopenia and physical prefrailty or frailty in England (MET-PREVENT): a double-blind, randomised, placebo-controlled trial Full Text
Metformin's Anticancer Odyssey: Revealing Multifaceted Mechanisms Across Diverse Neoplastic Terrains- A Critical Review Full Text
Opposite causal effects of type 2 diabetes and metformin on Alzheimer's disease Full Text

Rapamycin (sirolimus)
Ovarian cryopreservation with rapamycin improves fertility restoration in a murine orthotopic transplantation model Full Text
mTOR Inhibition limits LPS induced acute kidney injury and ameliorates hallmarks of cellular senescence Full Text
*Rapamycin enhances neurovascular, peripheral metabolic, and immune function in cognitively normal, middle-aged APOE4 Carriers: genotype-dependent effects compared to non-carriers Full Text PREPRINT

Miscellaneous Molecules & Prescription Drugs
*Impact of Disease-Modifying Antirheumatic Drugs on Cognitive Function in Older Adults with Rheumatoid Arthritis Full Text
*Sildenafil and risk of Alzheimer disease: a systematic review and meta-analysis Full Text
Neuroprotective effects of SGLT2 inhibitors empagliflozin and dapagliflozin on Aβ1–42-induced neurotoxicity and neuroinflammation in cellular models of Alzheimer's disease CAN

Novel Molecules
Elamipretide, a Potential New Drug, Reduces Frailty in Mice Full Text
3-Monothiopomalidomide, a new immunomodulatory imide drug (IMiD), blunts inflammation and mitigates ischemic stroke in the rat Full Text

Other Areas of Interest (in alphabetical order)

Ageing Clocks
*Chemical and Climatic Environmental Exposures and Epigenetic Aging: a Systematic Review Full Text
*Epigenetic Clocks Relate to Four Age-Related Health Outcomes Similarly across Three Countries Full Text
*Epigenetic age acceleration and mortality risk prediction in US adults Full Text

Blood Factors or other Heterochronic Transplantation
*Beneficial genetic changes observed in regular blood donors Full Text***

Epigenetics & Cellular Reprogramming
Conserved Biological Processes in Partial Cellular Reprogramming: Relevance to Aging and Rejuvenation Full Text
Epigenetic editing at individual age-associated CpGs affects the genome-wide epigenetic aging landscape Full Text

Exosomes (small packets of information released by cells)
Heme oxygenase 1‑overexpressing bone marrow mesenchymal stem cell‑derived exosomes suppress interleukin‑1 beta‑induced apoptosis and aging of nucleus pulposus cells Full Text
Extracellular Vesicles Restore Some Heart Function to Mice Full Text
Exosomal miR-499a-5p from human umbilical cord mesenchymal stem cells attenuates liver fibrosis via targeting ETS1/GPX4-mediated ferroptosis in hepatic stellate cells Full Text

Genetics including CRISPR
Genetically supported targets and drug repurposing for brain aging: A systematic study in the UK Biobank Full Text
Bcl-xL overexpression in T cells preserves muscle mitochondrial structure and function and prevents frailty in old mice Full Text
Beneficial effects of vascular endothelial growth factor B gene transfer in the aged heart Full Text

Lifespan Lengthening Interventions
High-content screening identifies ganoderic acid A as a senotherapeutic to prevent cellular senescence and extend healthspan in preclinical models Full Text
The Impact of Rosemary and Ginger Extracts on Aging and Healthspan in Drosophila Full Text
Association of α-Klotho with anti-Aging effects of Ganoderma lucidum in animal models
Chrysophanol delays aging via insulin/IGF-1 signaling pathway
β-hydroxy-β-methylbutyrate Attenuates Age-Dependent Loss of Flight Ability and Extends Lifespan in Drosophila Full Text

Microbiome
*Assessing the gut microbiota composition in older adults: connections to physical activity and healthy ageing Full Text
*The association between gut microbiota and accelerated aging and frailty: a Mendelian randomization study Full Text
Streptococcus thermophilus CNCM I-5570 lysate counteracts the aging process in human dermal fibroblast cells by neutralizing harmful free radicals and impacting antioxidant and anti-inflammatory pathways, thus restoring their physiological functions Full Text

Observational Studies
*Caregiving is Associated with Lower Brain Age in Humans Full Text
*BMI-for-age percentile curves for older adults Full Text CAN
*Personality Traits and Health Behaviors as Predictors of Fall Among Community-Dwelling Older Adults: Findings From the Canadian Longitudinal Study on Aging Full Text CAN
*Satisfaction with Life of Older Men and Women in the Canadian Longitudinal Study on Aging (CLSA) and its Association with Formal and Informal Home Care Full Text CAN

Opinion/Editorials/Theory/Policy
What Comes Next for Vitamin D Supplementation and Trials in Older Adults? Full Text
The ongoing challenge of slowing aging through drug discovery Full Text

Other Ageing Biology
Nicotinamide riboside and nicotinamide mononucleotide facilitate NAD+ synthesis via enterohepatic circulation Full Text
Drug-Based Lifespan Extension in Mice Strongly Affects Lipids Across Six Organs Full Text
A stress-dependent TDP-43 SUMOylation program preserves neuronal function Full Text CAN

Regenerative Medicine
Endodontic Regeneration Therapy: Current Strategies and Tissue Engineering Solutions Full Text

Reproductive Health
*Menopausal symptom burden as a predictor of mid- to late-life cognitive function and mild behavioral impairment symptoms: A CAN-PROTECT study Full Text CAN
*Semen quality and lifespan: a study of 78 284 men followed for up to 50 years Full Text
BDNF secreted by mesenchymal stem cells improves aged oocyte quality and development potential by activating the ERK1/2 pathway Full Text
*The efficacy of platelet-rich plasma (PRP) alone or in combination with low intensity shock wave therapy (Li-SWT) in treating erectile dysfunction: a systematic review and meta-analysis of seven randomized controlled trials Full Text

Reviews
Design principles of gene circuits for longevity Full Text
The time is now: accounting for time-of-day effects to improve reproducibility and translation of metabolism research Full Text
Dietary Polyphenols as Geroprotective Compounds: From Blue Zones to Hallmarks of Ageing Full Text
Xenotopic synthetic biology: Prospective tools for delaying aging and age-related diseases Full Text

Senolytics/Senescent Cells
p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells Full Text
Cellular Senescence Is a Central Driver of Cognitive Disparities in Aging Full Text

Skin & Beauty
Young fibroblast-derived migrasomes alleviate keratinocyte senescence and enhance wound healing in aged skin Full Text
*A Pilot Randomized Controlled Trial (RCT) Evaluating the Efficacy of an Exosome-Containing Plant Extract Formulation for Treating Male Alopecia Full Text
*A Single-center, Double-blinded, Randomized, Placebo-controlled Trial Evaluating the Safety and Efficacy of a Dietary Supplement Containing Rosemary Extract on Visible Facial Skin Quality Full Text
Targeting IGF1-Induced Cellular Senescence to Rejuvenate Hair Follicle Aging Full Text
Youthful Brain-Derived Extracellular Vesicle-Loaded GelMA Hydrogel Promotes Scarless Wound Healing in Aged Skin by Modulating Senescence and Mitochondrial Function Full Text

Stem Cells
Human umbilical cord-derived mesenchymal stem cells improve thymus and spleen functions in d-galactose-induced aged mice Full Text
Amniotic fluid-derived mesenchymal stem cells as a therapeutic tool against cytokine storm: a comparison with umbilical cord counterparts Full Text

Telomeres
The relationship between telomere length and aging-related diseases Full Text

Odds & Sods
*Home-based heat therapy lowers blood pressure and improves endothelial function in older adults Full Text
*Photobiomodulation improves functional recovery after mild traumatic brain injury Full Text
*Practice makes perfect, but to what end? Computerised brain training has limited cognitive benefits in healthy ageing 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.*
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------