August 2020 Longevity Review

Posted by Chris Pollyanna , 05 October 2020 · 2,014 views

supplements covid 19 senolytics nad+ gene therapy

Hello and welcome again to this month’s longevity review. August was another month of progress; however, I cannot shy away from the elephant in the room, which is the failure of the Unity senolytics trial for osteoarthritis. Although without a doubt a setback, it doesn’t invalidate the entire senolytic field. There are a hundred and one different reasons why a particular trial fails - from dosage to target selection and everything in between. Fortunately, there have already been a couple of successful trials using other compounds, which to my mind point to the great promise these therapies hold.

On a much more positive note, I was recently contacted by a reader of this newsletter, who also happens to be one of the authors of one of the most exciting studies to reach pre-print this year. In that study, which I wrote about in May’s review, rats had various biomarkers as well as their epigenetic age reversed. They are now moving forward to secure further funding and are launching “a SAFE Convertible round. It will convert at 20% discount to the valuation of the institutional round. It is open only to accredited investors.” If you are an accredited investor and potentially have an interest in investing, then please get in touch and I can pass on further details. I should note that I have zero financial connection to this (I don’t even understand the above quote!), do not stand to benefit and am merely passing this on as it has come from a reader.
Stay safe!
Follow me on Twitter @ChrisPollyanna1 for the latest updates.
And please join my longevity Facebook group.
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
NOTE: I’ve been having trouble linking to the science journal hacking site www.sci-hub.se , so am only including Full Text links to articles not behind a paywall. I still have been able to download most of them, so if there are any that you are after, I can send them upon request, or you can simply copy the paper’s URL into the site above to get +95% of papers hidden behind paywalls.

Round-Up:
There has been a recurring debate in the longevity community as to whether or not the loss of telomeres is a cause or consequence of ageing, and whether increasing their length could have a beneficial effect. In this study, by one of the leaders of the field, gene therapy was used to lengthen the telomeres of mice with beneficial effects on pulmonary fibrosis.
Towards a Telomerase Gene Therapy for Pulmonary Fibrosis Full Text Journal Club Video

Sticking with gene therapy, in this study it was used to improve the motor function and muscle strength of aged mice.
Gene Therapy Improves Motor Function in Aged Mice Full Text

The decline of our immune system is one of the main causes of age related dysfunction, and if it could be reversed a myriad of benefits would ensue. One potential avenue is via the Thymus, where our T-cells mature, and which shrinks with age. Here, researchers have reprogrammed and implanted some cells into the thymus which resulted in its regrowth and subsequent reduction in inflammation.
Researchers Rejuvenate the Thymi of Old Mice Full Text

I mentioned in the intro the failure of senolytic therapy in osteoarthritis. Maybe what was needed was not just the removal of senescent cells, but also their replacement with fresh stem cells to regrow the worn cartilage. In this study, stem cells have been used for just such a purpose, improving the mobility of the treated mice.
Stem Cells Produce Healthy Cartilage in Osteoarthritic Joints Abstract

I have long gone on about how combinations of treatments are the only way that ageing can be systematically treated. Here a peptide, SS-31 AKA Elamipretide, and an available supplement, NMN, have been shown to synergistically work together to improve the ageing heart of mice.
SS-31 and NMN: Two paths to improve metabolism and function in aged hearts Full Text

And finally, here is a study which I had meant to include last month but somehow slipped through the cracks. This study is about a novel molecule which has been derived from Fisetin, a supplement which I take and which is found in highest concentrations in strawberries. Here, this molecule has been found to reverse Alzheimer's-like memory decline in mice.
New molecule reverses Alzheimer's-like memory decline Full Text

COVID-19 Longevity Related Papers:

A Geroscience Approach to Preventing Pathologic Consequences of COVID-19 Full Text
Vitamin D Insufficiency and Deficiency and Mortality from Respiratory Diseases in a Cohort of Older Adults: Potential for Limiting the Death Toll during and beyond the COVID-19 Pandemic? Full Text
Revisiting the role of vitamin D levels in the prevention of COVID-19 infection and mortality in European countries post infections peak Full Text
Melatonin, Aging and COVID-19: Could melatonin be beneficial for COVID-19 treatment in elderly? Full Text PDF available

------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Videos to watch:
I mentioned last month that I volunteered at the excellent Ending Age Related Diseases 2020 conference. The videos for the conference have started to be posted, though be sure to check back in the future when they will all be eventually up.
Ending Age Related Diseases 2020 Presentation Videos
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Further sources of information:
Fight Aging! (quite opinionated about the damage theory of ageing)
Life Extension Advocacy Foundation (LEAF) (best source of longevity information on the web)
Longecity (good forums where the self-experimenters reside!)
Aging Matters (good blog from the programmed ageing side)
Research Institutes:
SENS Research Foundation (I have a recurring monthly donation)
Buck Institute
Private initiatives:
Age-Reversal Network (good information & forums for those interested in self-experimentation – this is where I found how to get non-prescription Rapamycin)
Better Humans
Gerontology Research Group
Lifespan.io (Tied together with LEAF, I have a recurring monthly donation)

=============================================================================================================================

2020 Supplemental Information

***Disclaimer 1 – As should be self-evident to anyone receiving these emails, 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 needing 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 below 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.*
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Lifestyle
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.
*Effect of 2 years of calorie restriction on liver biomarkers: results from the CALERIE phase 2 randomized controlled trial
*Effects of weight loss during a very low carbohydrate diet on specific adipose tissue depots and insulin sensitivity in older adults with obesity: a randomized clinical trial Full Text
*Intermittent Fasting Enhanced the Cognitive Function in Older Adults with Mild Cognitive Impairment by Inducing Biochemical and Metabolic changes: A 3-Year Progressive Study Full Text

Diet – let food be thy medicine…
*Protective Effects of Polyphenols Present in Mediterranean Diet on Endothelial Dysfunction Full Text
*Higher Adherence to the Mediterranean Diet Is Associated With Preserved White Matter Integrity and Altered Structural Connectivity Full Text
*The Effect of Healthy Diet on Cognitive Performance Among Healthy Seniors - A Mini Review Full Text

Exercise – if you could bottle the benefits of exercise, it would be the biggest blockbuster drug of all time.
*Maintenance of muscle strength following a one-year resistance training program in older adults
*A single bout of moderate intensity exercise improves cognitive flexibility: evidence from task-switching Full Text
*Effectiveness of a resistance training program on physical function, muscle strength, and body composition in community-dwelling older adults receiving home care: a cluster-randomized controlled trial Full Text

Non-prescription Supplements (in alphabetical order)
*Due to concerns about engendering homeostasis, I’ve begun varying my intake of supplements so that I’m not taking all of them every day. Haven’t worked out a rota so far.
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. I take 4 or 8 mg intermittently.
*The effects of astaxanthin supplementation on obesity, blood pressure, CRP, glycemic biomarkers, and lipid profile: A meta-analysis of randomized controlled trials
Purified Astaxanthin from Haematococcus pluvialis Promotes Tissue Regeneration by Reducing Oxidative Stress and the Secretion of Collagen In Vitro and In Vivo Full Text
Astaxanthin promotes M2 macrophages and attenuates cardiac remodeling after myocardial infarction by suppression inflammation in rats Full Text

Curcumin – the spice which gives curries their yellow colour. Anti-inflammatory and neuroprotective. I take 1 gram intermittently. Needs to be taken with black pepper (piperine) to improve bioavailability.
*The Efficacy and Safety of Highly-Bioavailable Curcumin for Treating Knee Osteoarthritis: A 6-Month Open-Labeled Prospective Study Full Text
*Clinical effects of curcumin in enhancing cancer therapy: A systematic review Full Text
Interaction between Gut Microbiota and Curcumin: A New Key of Understanding for the Health Effects of Curcumin Full Text

Fisetin – a flavonoid found in highest concentrations in strawberries. Senolytic, anti-inflammatory, anti-cancer, neuro-protective & Sirt1 activator. I take 100mg intermittently and will soon be trying a high dose senolytic n=1 trial.
Fisetin Alleviates Hepatic and Adipocyte Fibrosis and Insulin Resistance in Diet-Induced Obese Mice
SIRT1 Activation by Natural Phytochemicals: An Overview Full Text

Melatonin – a natural hormone produced in the pineal gland, it makes us get to sleep every night, but it has many other functions, including as a mitochondrial antioxidant. I’ve been taking 3mg for years before bed time purely as a sleep aid, but I’ve recently noticed it repeatedly cropping up in my longevity searches so decided to include it in its own section.
Melatonin's Impact on Antioxidative and Anti-Inflammatory Reprogramming in Homeostasis and Disease Full Text
Melatonin Protects HT22 Hippocampal Cells from H2O2-induced Injury by Increasing Beclin1 and Atg Protein Levels to Activate Autophagy

Nicotinamide MonoNucleotide (NMN) – newer NAD+ precursor. I take 250 – 500mg on days I exercise.
Nicotinamide Mononucleotide Supplementation Reverses the Declining Quality of Maternally Aged Oocytes Full Text
Mitochondrial DNA mutation exacerbates female reproductive aging via impairment of the NADH/NAD + redox Full Text

Nicotinamide Riboside (NR) – NAD+ precursor.
*Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI Full Text
*Boosting NAD Level Suppresses Inflammatory Activation of PBMC in Heart Failure Full Text
Systemic Treatment With Nicotinamide Riboside Is Protective in a Mouse Model of Light-Induced Retinal Degeneration Full Text

Pterostilbene – found in blueberries. Anti-oxidant, anti-inflammatory and Sir1 activator. Similar to, but with greater bioavailability than resveratrol. Taking 50mg intermittently in the same pill as resveratrol. Works better in conjunction with NAD+ precursors.
Pterostilbene Attenuates Cocultured BV-2 Microglial Inflammation-Mediated SH-SY5Y Neuronal Oxidative Injury via SIRT-1 Signalling Full Text

Resveratrol – found in the skin of grapes. Anti-oxidant, anti-inflammatory and Sir1 activator. Taking 250mg intermittently in the same pill as pterostilbene. Works better in conjunction with NAD+ precursors & Spermidine.
*Long-term effects of resveratrol on cognition, cerebrovascular function and cardio-metabolic markers in postmenopausal women: A 24-month randomised, double-blind, placebo-controlled, crossover study
*Long-term resveratrol supplementation improves pain perception, menopausal symptoms, and overall well-being in postmenopausal women: findings from a 24-month randomized, controlled, crossover trial Video Overview
Resveratrol improves sperm DNA quality and reproductive capacity in type 1 diabetes

Spermidine – found in wheat germ and a potent inducer of autophagy, it works in synergy with Resveratrol. I try to eat a few teaspoons of wheat germ every day in my berry & nut breakfast.
Spermidine-induced improvement of memory consolidation involves PI3K/Akt signaling pathway
Spermidine, an autophagy inducer, as a therapeutic strategy in neurological disorders

Other available supplements (in alphabetical order) & combinations
Antioxidant Apigenin Relieves Age-Related Muscle Atrophy by Inhibiting Oxidative Stress and Hyperactive Mitophagy and Apoptosis in Skeletal Muscle of Mice Full Text
Vitamin D supplementation: upper limit for safety revisited? Full Text
Fish oil supplementation attenuates cognitive impairment by inhibiting neuroinflammation in STZ-induced diabetic rats Full Text
The Potential Effects of Probiotics and ω-3 Fatty Acids on Chronic Low-Grade Inflammation Full Text
*Long-term Effects of Calcium β-Hydroxy-β-methylbutyrate (HMB) and Vitamin D3 Supplementation on Muscular Function in Older Adults with and without Resistance Training: A Randomized, Double-blind, Controlled Study Full Text
Lycopene - A pleiotropic neuroprotective nutraceutical: Deciphering its therapeutic potentials in broad spectrum neurological disorders
Piceatannol, a Natural Analog of Resveratrol, Exerts Anti-angiogenic Efficiencies by Blockage of Vascular Endothelial Growth Factor Binding to Its Receptor Full Text

Prescription Supplements
Metformin – Anti-diabetic medication, maintained by many scientists to be a safe longevity enhancing medication. I’m still on the fence about this.
Metformin, resveratrol, and exendin-4 inhibit high phosphate-induced vascular calcification via AMPK-RANKL signaling
Metformin attenuates renal interstitial fibrosis through upregulation of Deptor in unilateral ureteral obstruction in rats Full Text

Rapamycin (sirolimus) – first drug proven to increase the health & lifespan of mice. Currently used for organ transplantation and against cancer.
Sex differences in changes of protein synthesis with rapamycin treatment are minimized when metformin is added to rapamycin
Rapamycin Pretreatment Alleviates Cerebral Ischemia/Reperfusion Injury in Dose-Response Manner Through Inhibition of the Autophagy and NFκB Pathways in Rats Full Text
Rapamycin Inhibited Pyroptosis and Reduced the Release of IL-1 β and IL-18 in the Septic Response Full Text

Other Areas of Interest (in alphabetical order)
Ageing Clocks & other biomarkers of ageing – the ability to measure biological ageing is crucial if we don’t want to have to wait 20+ years for the results of an anti-ageing intervention:
RNAAgeCalc: A multi-tissue transcriptional age calculator Full Text
Epigenetic age and pregnancy outcomes: GrimAge acceleration is associated with shorter gestational length and lower birthweight Full Text
MetaboAge DB: a repository of known ageing-related changes in the human metabolome Full Text

Lifespan Lengthening Interventions - any intervention which lengthens the lifespan and/or healthspan of model organisms.
Astragaloside IV Extends Lifespan of Caenorhabditis elegans by Improving Age-Related Functional Declines and Triggering Antioxidant Responses Full Text
Inhibition of Cdc42 activity extends lifespan and decreases circulating inflammatory cytokines in aged female C57BL/6 mice Full Text
Fluctuating temperatures extend median lifespan, improve reproduction and reduce growth in turquoise killifish
VPS-22/SNF8 regulates longevity via modulating the activity of DAF-16 in C. elegans
Dietary magnesium supplementation improves lifespan in a mouse model of progeria Full Text
Life span extension by glucose restriction is abrogated by methionine supplementation: Cross-talk between glucose and methionine and implication of methionine as a key regulator of life span Full Text
Antistress and anti-aging activities of Caenorhabditis elegans were enhanced by Momordica saponin extract

Microbiome – all the little critters living in and on us have a major influence on our health and potentially our longevity.
Microbiota-host interactions shape ageing dynamics Full Text
The Gut Microbiota and Unhealthy Aging: Disentangling Cause from Consequence Full Text
Relationship between Diet, Microbiota, and Healthy Aging Full Text

Reviews
Reproductive Longevity and Aging: Geroscience Approaches to Maintain Long-Term Ovarian Fitness Full Text
The interplay between immunosenescence and age-related diseases Full Text
The role of the stem cell epigenome in normal aging and rejuvenative therapy Full Text

Senolytics – not supplements or available now, but the most exciting area of anti-research at the moment. I intend to take the plunge into senolytics within the next year, before giving them to my parents:
Rejuvenating old organs could increase donor pool Full Text
Senolytic activity of small molecular polyphenols from olive restores chondrocyte redifferentiation and promotes a pro-regenerative environment in osteoarthritis Full Text

Skin & Beauty – not naming any names, but I’m sure that some of you also care about superficial ageing – how our skin looks. ;-) Having said that, it is our largest organ & the treatments which keep on cropping up could be of use to some people.
Hyaluronic acid-based two-stage medical therapy to unfold the aged face: The centrifugal approach
A Randomized, Triple-Blind, Placebo-Controlled, Parallel Study to Evaluate the Efficacy of a Freshwater Marine Collagen on Skin Wrinkles and Elasticity

Stem Cells & Exosomes (small packets of information released by cells)
Effects of bone marrow mesenchymal stem cells on ovarian and testicular function in aging Sprague-Dawley rats induced by D-galactose
Mesenchymal stromal cells for articular cartilage repair: preclinical studies Full Text
Stem Cells of the Aging Brain Full Text

Telomeres – the protective caps on the end of our chromosomes. Their shortening over time has been seen by some as either an ageing “clock”, or indeed as a driver of ageing itself, however, this is a controversial viewpoint.
Why women may live longer than men do? A telomere-length regulated and diet-based entropic assessment
U-shaped relationship of leucocyte telomere length with all-cause and cancer-related mortality in older men

Young Blood Factors or other heterochronic transplantation – another potential “silver bullet” against ageing based on the discovery that young blood seems to rejuvenate older animals and vice versa. The race is on to discover what components in blood cause these changes and if they can be applied to humans:
Effects of heterochronic, non-myeloablative bone marrow transplantation on age-related behavioural changes in mice
Efficient Strategies for Microglia Replacement in the Central Nervous System Full Text