April 2022 Longevity Review

Although not as crazy as March, April nonetheless trumped March by producing the preprint paper I’ve been waiting a long time for - the combination of two major longevity modalities for the first time: senolytics and partial-reprogramming. I’ve said it a thousand times and I’ll say it several thousand times more: we will only make a large impact on ageing when we successfully combine different treatments, and the paper you’ll find in April’s Round-Up demonstrates that by showing a synergistic improvement in both health and lifespan.

Some extra highlights from the supplemental section include another partial reprogramming paper, this time on the liver, a few more senolytic papers, and there were also new clinical trial results for NMN and Resveratrol. In addition a couple of articles came out about combining calorie restriction with time restricted eating, so be sure to check them out if you’re planning on losing weight following that method.

This month I’ve also added a Reproductive Health section, the prior lack of which probably stems from my own disinclination to have children. However, since this area is often under-represented in the longevity field, it is time to correct that.

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CLA News

Apart from holding another monthly meetup, gaining a couple more volunteers and continuing with the background infrastructure development, the big news is that we’ve finally set up a CLA YouTube channel and posted the first video. For years I’ve been thinking that I should do an online walkthrough of this Longevity Review. Well, I finally did it using Facebook Live, and although the first one was very much a test (and it shows! LOL), I will be doing this on a monthly basis going forward. Please subscribe to the channel! Canadian Longevity Association YouTube Channel

Canadian Longevity Spotlight

Although I’ve mentioned them before, YOUAREUNLTD are Canadian partners in the fight against ageing. Having met the leadership team, I can say that they fully understand the potential of a longevity economy and the CLA will be collaborating with them going forward. There are some good articles on their site, so be sure to check them out.

YOUAREUNLTD

April 2022 Round-Up:

I normally don’t post about studies before they have passed peer review, but this one is significant enough for me to break that rule. Here, for the first time, two of the biggest areas of longevity research, senolytics and partial reprogramming, have been combined to produce synergistic life and health extension results. Although only in flies, this combo should be available for us in the 2030s.
Combining Stem Cell Rejuvenation and Senescence Targeting to Synergistically Extend Lifespan Full Text Lifespan.io Analysis

Although not technically against ageing, since obesity is such an age accelerant and proximal cause of many ageing related diseases, and not to mention unfortunately difficult to combat through lifestyle interventions, anything that can assist with reducing weight could prove to be beneficial - especially if we are talking about a 20% reduction, as is the case here.
GIP/GLP-1 Receptor Agonist Slashes Body Weight by More Than 20% Press Release

Here, my favourite longevity drug, Rapamycin, has been teamed up with Caloric Restriction (CR) to produce additive benefits. For a long time Rapamycin has been assumed to merely be a CR mimetic, which I have disagreed with, and this paper is another nail in that coffin. As a bonus, it also involves a combination of treatments, which as you know is the future of longevity treatments.
Multiple treatments to slow age-related muscle wasting Lifespan.io Analysis Full Text

Here is a relatively simple and very actionable combination of treatments which appear to slash the risk of developing invasive cancer in the over seventies. One benefit of this study, which increases confidence in it, is that it had a relatively large number of participants compared to most studies of its ilk.
*A combination of three simple treatments may reduce invasive cancer risk by 61% among adults aged 70+ Full Text

Ending with an another actionable paper, this time a short overview of a potential longevity diet from Valter Longo, an expert in the field and the guy behind the Fasting Mimicking Diet
*New article outlines the characteristics of a 'longevity diet' Full Text

Supplemental Section

Lifestyle
*Healthy lifestyle and life expectancy with and without Alzheimer’s dementia: population based cohort study Full Text
*Comparison of Two Diet and Exercise Approaches on Weight Loss and Health Outcomes in Obese Women 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.
*Early time-restricted eating compared with daily caloric restriction: A randomized trial in adults with obesity Full Text
*Is a Combined Calorie- and Time-Restricted Diet Best? Abstract
*Development and Evaluation of Integrated Chrono-Nutrition Weight Reduction Program among Overweight/Obese with Morning and Evening Chronotypes Full Text

Diet – let food be thy medicine…
*Epigenetic Effects of Healthy Foods and Lifestyle Habits From The Southern European Atlantic Diet Pattern: A Narrative Review Full Text
Vegetables and Their Bioactive Compounds as Anti-Aging Drugs Full Text

Exercise – if you could bottle the benefits of exercise, it would be the biggest blockbuster drug of all time.
*Physical activity attenuates but does not eliminate coronary heart disease risk amongst adults with risk factors: EPIC-CVD case-cohort study Full Text
*Dose-response association between step count and cardiovascular disease risk markers in middle-aged adults Full Text
*Effect of High Intensity Power Training on Cognitive Function in Older Adults with Type 2 Diabetes: Secondary Outcomes of the GREAT2DO Study 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 delays brain aging in senescence-accelerated mouse prone 10: inducing autophagy as a potential mechanism
The Effect of Two Different Doses of Astaxanthin on Alveolar Bone Loss in an Experimental Model of Periodontitis in Diabetic Rats
Astaxanthin Modulates Autophagy, Apoptosis, and Neuronal Oxidative Stress in a Rat Model of Compression Spinal Cord Injury

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 Curcumin Supplementation with Piperine Can Influence the Acute Elevation of Exercise-Induced Cytokines: Double-Blind Crossover Study Full Text
*The effects of curcumin on anthropometric and cardiometabolic parameters of patients with metabolic related diseases: a systematic review and dose-effect meta-analysis of randomized controlled trials
*The effect of curcumin on the risk of mortality in patients with COVID-19: A systematic review and meta-analysis of randomized trials Full Text

Fisetin
Effects of Fisetin on Allergic Contact Dermatitis via Regulating the Balance of Th17/Treg in Mice Full Text
Characterization of induction and targeting of senescent mesenchymal stromal cells
Long-term administration of fisetin was not as effective as short term in ameliorating IR injury in isolated rat heart 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.
*Controlled-release oral melatonin supplementation for hypertension and nocturnal hypertension: A systematic review and meta-analysis Full Text
*The Dose- and Duration-Dependent Association between Melatonin Treatment and Overall Cognition in Alzheimer's Dementia: A Network Meta-Analysis of Randomized Placebo-Controlled Trials
Beneficial effects of melatonin on liver fibrosis: A systematic review of current biological evidence Full Text

Nicotinamide MonoNucleotide (NMN)
*Oral Administration of Nicotinamide Mononucleotide Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide Levels in Healthy Subjects Full Text
*Nicotinamide mononucleotide (NMN) as an anti-aging health product – Promises and safety concerns Full Text (August 2021)
Supplementation of nicotinamide mononucleotide improves the quality of postovulatory aged porcine oocytes Full Text

Nicotinamide Riboside (NR)
Nicotinamide riboside relieves the severity of experimental necrotizing enterocolitis by regulating endothelial function via eNOS deacetylation
Sirtuin 3 Dependent and Independent Effects of NAD+ to Suppress Vascular Inflammation and Improve Endothelial Function in Mice Full Text

Pterostilbene
Pterostilbene and Its Derivative 3′-Hydroxypterostilbene Ameliorated Nonalcoholic Fatty Liver Disease Through Synergistic Modulation of the Gut Microbiota and SIRT1/AMPK Signaling Pathway
SIRT1 Is Involved in the Neuroprotection of Pterostilbene Against Amyloid β 25–35-Induced Cognitive Deficits in Mice Full Text
Thioredoxin-1 Activation by Pterostilbene Protects Against Doxorubicin-Induced Hepatotoxicity via Inhibiting the NLRP3 Inflammasome Full Text

Resveratrol
*Resveratrol Inhibits Metabolism and Affects Blood Platelet Function in Type 2 Diabetes Full Text
*Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review Full Text (March 2022)
Benefits and Implications of Resveratrol Supplementation on Microbiota Modulations: A Systematic Review of the Literature Full Text

Other available supplements (in alphabetical order)
*Bis Hexanoyl ®-1,3-Butanediol, a Novel Ketogenic Ester, Acutely Increases Circulating r- and s-ß-Hydroxybutyrate Concentrations in Healthy Adults Full Text (March 2022)
Marijuana linked to heart disease; supplement may mitigate risk, researchers report Abstract
*The effect of krill oil supplementation on skeletal muscle function and size in older adults: A randomised controlled trial Full Text
*A ketogenic intervention improves dorsal attention network functional and structural connectivity in mild cognitive impairment Full Text
Health Benefits of Quercetin in Age-Related Diseases Full Text

Combinations of Supplements/Treatments
*Effect of a Fixed Combination of Curcumin, Artemisia, Bromelain, and Black Pepper Oral Administration on Optical Coherence Tomography Angiography Indices in Patients with Diabetic Macular Edema Full Text*
*Potential Benefits of Combined Statin and Metformin Therapy on Resistance Training Response in Older Individuals Full Text*
Pan-mTOR inhibitors sensitize the senolytic activity of Navitoclax via mTORC2 inhibition-mediated apoptotic signaling

Prescription Supplements

Metformin
*Evaluation for clinical benefit of metformin in patients with idiopathic pulmonary fibrosis and type 2 diabetes mellitus: a national claims-based cohort analysis Full Text
*Metformin use is associated with low risk of case fatality and disability rates in first-ever stroke patients with type 2 diabetes Full Text
*Association between metformin use and the risk of age-related macular degeneration in patients with type 2 diabetes: a retrospective study Full Text

Rapamycin (sirolimus)
*Sirolimus leads to rapid and sustained clinical improvement of motor deficits in a patient with inclusion body myositis Full Text
Rapamycin improves the quality and developmental competence of mice oocytes by promoting DNA damage repair during in vitro maturation Full Text
Dietary Restriction and Rapamycin Affect Brain Aging in Mice by Attenuating Age-Related DNA Methylation Changes Full Text
The mTOR inhibitor Rapamycin protects from premature cellular senescence early after experimental kidney transplantation Full Text
The Topical Ocular Delivery of Rapamycin to Posterior Eye Tissues and the Suppression of Retinal Inflammatory Disease Full Text

Miscellaneous Molecules
*Breakthrough in treatment for Dupuytren's disease Full Text
Liraglutide preserves CD34+ stem cells from dysfunction Induced by high glucose exposure Full Text
SGLT2 inhibition attenuates arterial dysfunction and decreases vascular F-actin content and expression of proteins associated with oxidative stress in aged mice Full Text
SS31 Ameliorates Oxidative Stress via the Restoration of Autophagic Flux to Protect Aged Mice From Hind Limb Ischemia Full Text
Inhibition of RIPK1 by ZJU-37 promotes oligodendrocyte progenitor proliferation and remyelination via NF-κB pathway Full Text

Other Areas of Interest (in alphabetical order)

Ageing Clocks & other biomarkers of ageing
Automated, high-dimensional evaluation of physiological aging and resilience in outbred mice Full Text
*Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume Full Text
*Salivary Proteome, Inflammatory, and NETosis Biomarkers in Older Adult Practitioners and Nonpractitioners of Physical Exercise Full Text

Blood Factors or other Heterochronic Transplantation
Heterochronic parabiosis: a valuable tool to investigate cellular senescence and other hallmarks of aging Full Text
The Influence of Heterochronic Non-Myeloablative Bone Marrow Transplantation on the Immune System, Frailty, General Health, and Longevity of Aged Murine Recipients Full Text

Epigenetics & Cellular Reprogramming
*Accelerated biological aging in COVID-19 patients Full Text
Cellular regeneration therapy restores damaged liver tissue faster than ever Lifespan.io Analysis Full Text
Natural killer cells act as an extrinsic barrier for in vivo reprogramming Full Text

Exosomes (small packets of information released by cells)
Juvenile Plasma Factors Improve Organ Function and Survival following Injury by Promoting Antioxidant Response Full Text
Hypoxic pretreatment of adipose-derived stem cell exosomes improved cognition by delivery of circ-Epc1 and shifting microglial M1/M2 polarization in an Alzheimer’s disease mice model Full Text
Exercise, healthy ageing, and the potential role of small extracellular vesicles Full Text

Genetics including CRISPR
*Experimental ‘gene silencing’ therapy reduces lipoprotein(a), an important risk factor of heart disease, by up to 98% Abstract
Mutations across species reveal clues to ageing Lifespan.io Analysis Full Text
Immunity and lifespan: answering long-standing questions with comparative genomics Full Text
AAV-ie-K558R mediated cochlear gene therapy and hair cell regeneration Full Text

Lifespan Lengthening Interventions
S-adenosyl-L-homocysteine extends lifespan through methionine restriction effects Full Text
Hawthorn extract inhibited the PI3k/Akt pathway to prolong the lifespan of Drosophila melanogaster
FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice Full Text
Fundamental Protein Regulator Increases Lifespan in Flies Full Text
Cannabidiol Increases Lifespan and Healthspan in Worms Full Text

Microbiome
Fecal transplants reverse hallmarks of aging Lifespan.io Analysis Full Text
Lactobacillus paracasei PS23 improves cognitive deficits via modulating the hippocampal gene expression and the gut microbiota in d-galactose-induced aging mice Full Text
*The gut microbiome as a modulator of healthy ageing Full Text

Observational Studies
*Seven hours of sleep is optimal in middle and old age, say researchers Abstract
*Dermal advanced glycation end-product accumulation is associated with sarcopenia-related measures in middle-aged and older men Full Text
*Association of Cumulative Blood Pressure With Cognitive Decline, Dementia, and Mortality Full Text

Opinion/Editorials/Theory
Does Modulation of an Epigenetic Clock Define a Geroprotector? Full Text
Considerations Regarding Public Use of Longevity Interventions Full Text
Why animal model studies are lost in translation Full Text
Atlos Labs and the quest for immortality: but can we live longer right now? Full Text
Resilience integrates concepts in aging research Full Text
Genetic basis of cardiovascular aging is at the core of human longevity Full Text

Other Ageing Biology
Researchers find new strategy for preventing clogged arteries Full Text
rDNA array length is a major determinant of replicative lifespan in budding yeast Full Text
Chronic stress increases transcriptomic indicators of biological aging in mouse bone marrow leukocytes Full Text

Regenerative Medicine
A biomimetic and bioactive scaffold with intelligently pulsatile teriparatide delivery for local and systemic osteoporosis regeneration Full Text
Integrating the Synergy of the Gut Microbiome into Regenerative Medicine: Relevance to Neurological Disorders Full Text

Reproductive Health
Small Molecule Protects Against Oxidative Aging in Egg Cells Full Text
Senolytic treatment reverses obesity-mediated senescent cell accumulation in the ovary
Procyanidin B2 Protects Aged Oocytes Against Meiotic Defects Through Cortical Tension Modulation Full Text

Reviews
The Therapeutic Potential of tRNA-derived Small RNAs in Neurodegenerative Disorders full Text
Nutrition, metabolism, and epigenetics: pathways of circadian reprogramming Full Text
Novel Insights into the Roles and Mechanisms of GLP-1 Receptor Agonists against Aging-Related Diseases Full Text

Senolytics/Senescent Cells
Combining adoptive NK cell infusion with a dopamine-releasing peptide reduces senescent cells in aged mice Full Text
Short-term senolytic treatment: a paradigm to promote fracture repair during aging Lifespan.io Analysis Full Text
Mitochondrially targeted tamoxifen alleviates markers of obesity and type 2 diabetes mellitus in mice Full Text

Skin & Beauty
*A Topical Emollient Mitigates the Progression of Cognitive Impairment in the Elderly: A Randomized, Open-Label Pilot Trial
Oral Intake of Chicken Bone Collagen Peptides Anti-Skin Aging in Mice by Regulating Collagen Degradation and Synthesis, Inhibiting Inflammation and Activating Lysosomes Full Text

Stem Cells
LncRNA LYPLAL1-AS1 rejuvenates human adipose-derived mesenchymal stem cell senescence via transcriptional MIRLET7B inactivation Full Text
Mesenchymal Stem/Stromal Cell Senescence: Hallmarks, Mechanisms, and Combating Strategies Full Text
Mesenchymal stem cell treatment restores liver macrophages homeostasis to alleviate mouse acute liver injury revealed by single-cell analysis Full Text

Telomeres
*Stop the clocks: Brisk walking may slow biological aging process, study shows Full Text
*Association between sleep parameters and longitudinal shortening of telomere length Full Text

Odds & Sods
Once-daily feeding is associated with better health in companion dogs: results from the Dog Aging Project
*Effects of Prefrontal Transcranial Direct Current Stimulation on Retention of Performance Gains on an Obstacle Negotiation Task in Older Adults
*Working Memory Training Coupled With Transcranial Direct Current Stimulation in Older Adults: A Randomized Controlled Experiment Full Text
*Relieving Chronic Musculoskeletal Pain in Older Adults Using Transcranial Direct Current Stimulation: Effects on Pain Intensity, Quality, and Pain-Related Outcomes Full Text
*Effects of exergaming on executive function of older adults: a systematic review and meta-analysis Full Text
Epigenetic clock and methylation studies in marsupials: opossums, Tasmanian devils, kangaroos, and wallabies Full Text
Large and expensive brain comes with a short lifespan: The relationship between brain size and longevity among fish taxa

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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 *bolded any human trials.*
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