September 2019 Longevity Review

September 2019 Longevity Review

Hello and welcome once again to this month’s longevity update. September has turned out to be one of those month’s where several noteworthy advances have occurred, so that I can’t really decide which is the most important (see round-up below). It’s a great conundrum to have!

On a personally level, my parents have now started their regime, but I got a shock when it emerged from a forum that the Rapamycin they are taking might not be legit. In a subsequent development it appears that there is perhaps Rapamycin in the pills, albeit at a lower dose than advertised - 3.25mg instead of 5mg. Caveat emptor, and just shows the potential pitfalls of being at the cutting edge of self-experimentation before new drugs have been fully approved for an anti-ageing indication. This is also one reason why I have not been actively recommending their use or detailing how I obtained them. However, we all know with certainty what doing nothing at all will eventually result in…

On a more positive note, I’m slowly organizing here in Toronto: created a local Facebook group the “Toronto Longevity Association” and we’re going to be having our first monthly meet-up on October 30^th, feel free to join the group even if you are not a local, and if you are, please come along on the 30^th. Also, LEAF has asked me to collaborate with them on their monthly news round-up. To start with, I’ll be providing them with sources of information, but we’ll see where this leads…

Follow me on Twitter @ChrisPollyanna1 for the latest updates!
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NOTE: I’ve been having trouble linking to the science journal hacking site www.sci-hub.tw , 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.

September Round-Up:

• One of the most important developments of the year has been the release of the first in-human senolytic trial results, first in COPD in January and then in Osteoarthritis in June. However, those small trials could not prove that senescent cells had in fact been removed and that it was not some other mechanism behind their results. In this third trial, using Quercetin & Dasatinib in kidney disease, this was shown for the first time, although efficacy results await a future publication. The significance is that the mode of action appears to be the same as it is in mice, which is incredibly encouraging, as the results in mice have been nothing short of spectacular. Keep your eyes peeled for future results because senolytics could well be the first treatment available which could actually reverse certain aspects of ageing.

• In recent years the epigenetic clock has emerged as a means of assessing someone’s biological, as opposed to chronological, age. This very small trial used a cocktail of two drugs and Human Growth Hormone to increase the size of the thymus, an organ where immune cells go to mature and which atrophies with age. When the researchers measured the subjects’ epigenetic age before and one year after the trial, to their surprise, rather than increasing by a year, it decreased by one and a half - theoretically indicating an age reversal of 2.5 years! I must stress that this was a tiny trial of only 9 people, but this is the first time that epigenetic clock reversal has been documented in humans.

• OK, this result is in fruit flies, but it is still extremely significant. You might remember that I’ve been banging on about how treatments need to be combined if we’re going to see a sizable effect. So far, such as in this study from last year, the results of combining treatments has been additive, however in this new study, we are seeing synergistic effects ie the sum of the improvement is greater than its parts. Here three molecules: Rapamycin, Lithium & Trametinib each increased lifespan by around 11%, however, when combined this increased to 48%! In addition, Lithium cancelled out some potentially undesirable metabolic effects of Rapamycin.

• Although not directly related to longevity, this impressive advance nevertheless could prove to be incredibly important in speeding up the drug discovery process, which typically takes quite a long time. If it could be sped up, then new longevity medicines could reach the market sooner. Here researchers have used artificial intelligence to produce a novel drug from scratch in 21 days, which is unheard of. Even more helpful is that the company behind this, Insilico Medicine, is a leading player in the longevity field.

• Moving on from drug discovery to the drug approval process, the following news is significant because for the first time a drug trial targeting ageing itself is about to be launched, which has not been possible before. It has taken years of effort to first convince the FDA of its merits and then to get the necessary funding together. Although I might not think much of the drug in question (Metformin – see the supplementary section for why), it will make it easier for future, more effective drugs to be approved. And that is to the benefit of us all.

Lifespan.io MitoMouse Crowdfunding Campaign!

Requiring its own subsection is an exciting longevity initiative which YOU can help out with.

Despite the dramatic advances I have detailed in these newsletters, the longevity field remains chronically underfunded, which means that even crowdfunding campaigns can help produce meaningful science. This particular initiative is looking at a novel method to protect our mitochondria (the energy producers in our cells) by transferring their DNA into the nucleus of the cell. Don’t worry about the details – just get out your wallets and donate! The campaign runs until the end of the month and they have already reached their initial goal of $50K, but please help them reach their stretch goals and get more meaningful science done. I’ve donated $70 & will receive a lovely T-shirt & pen in return, but even a measly $10 would make a difference.

MitoMouse – Curing Mitochondrial Dysfunction in Mammals Crowd Funding & Donation Page

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Videos to watch & Book to read:

In a slight departure from previous newsletters, I want to introduce a newly published book which I highly recommend everyone to read: "Lifespan: Why We Age and Why We Don't Have To" by Dr. David Sinclair, who has featured in previously recommended videos. In his very readable book, he outlines his new theory on why we age based on over 20 years of work – the Information Theory of Ageing. More significantly, this theory potentially offers a short-cut to true rejuvenation. This is in line with my own belief that epigenetic cellular reprogramming is the next big thing in ageing research. However, this book is not just about theory, as he also delves into current best practices & near term anti-ageing solutions. Most importantly, he also shares my unbridled optimism about where longevity research will take us in the not too distant future.
Google Talk by David Sinclair – in which he outlines his theories & gives a small update on his research post-book publication.
Interview by Dr. Mercola – seemed the best & most in-depth out of the several podcasts interviewing Sinclair that I watched.
LEAF Webinar with David Sinclair including the author reading extracts from the book – I watched this one live.

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September 2019 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.*
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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.
Diet – let food be thy medicine…
*Lower carbohydrate diets and all-cause and cause-specific mortality: a population-based cohort study and pooling of prospective studies. Full Text
*Mediterranean diet: The role of long-chain ω-3 fatty acids in fish; polyphenols in fruits, vegetables, cereals, coffee, tea, cacao and wine; probiotics and vitamins in prevention of stroke, age-related cognitive decline, and Alzheimer disease.
*Marine Omega-3 Supplementation and Cardiovascular Disease: An Updated Meta-Analysis of 13 Randomized Controlled Trials Involving 127 477 Participants. Full Text
*Adherence to a healthy lifestyle counteracts the negative effects of risk factors on all-cause mortality in the oldest-old. Full Text
*Green tea and coffee intake and risk of cognitive decline in older adults: the National Institute for Longevity Sciences, Longitudinal Study of Aging.
*Dietary n-3 polyunsaturated fatty acids, fish intake and healthy ageing
Exercise – if you could bottle the benefits of exercise, it would be the biggest blockbuster drug of all time.
*Differential Effects of Physical Exercise, Cognitive Training, and Mindfulness Practice on Serum BDNF Levels in Healthy Older Adults: A Randomized Controlled Intervention Study.
*Effects of resistance training concentric velocity on older adults' functional capacity: A systematic review and meta-analysis of randomised trials.
*The influence of the Pilates method on quality of life and bone remodelling in older women: a controlled study.
Physical Activity and Brain Health Full Text
*Exercise and Arterial Stiffness in the Elderly: A Combined Cross-Sectional and Randomized Controlled Trial (EXAMIN AGE). Full Text
*Effects of sedentary behavior and physical activity on sleep quality in older people: A cross-sectional study.
*Age-Dependent Impairment in Endothelial Function and Arterial Stiffness in Former High Class Male Athletes Is No Different to That in Men With No History of Physical Training. Full Text
*Effects of interval training on quality of life and cardiometabolic risk markers in older adults: a 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 carotinoid, it has anti-oxidative, anti-inflamatory, anti-cancer, neuro-protective and skin-protective qualities. I take 4 or 8 mg intermittently.
Astaxanthin Protects OTA-Induced Lung Injury in Mice through the Nrf2/NF-κB Pathway Full Text
Combined intake of astaxanthin, β-carotene, and resveratrol elevates protein synthesis during muscle hypertrophy in mice. Full Text
Investigation of Astaxanthin Effect on Cisplatin Ototoxicity in Rats by Using Otoacoustic Emission, Total Antioxidant Capacity, and Histopathological Methods Full Text
Astaxanthin Ameliorates the Lipopolysaccharides-Induced Subfertility in Mouse via Nrf2/HO-1 Antioxidant Pathway. Full Text
Astaxanthin Modulation of Signaling Pathways That Regulate Autophagy 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 bio-availability.
*Effect of curcumin nanomicelle on the clinical symptoms of patients with rheumatoid arthritis: A randomized, double-blind, controlled trial.
Dietary Curcumin: Correlation between Bioavailability and Health Potential. Full Text
*Curcumin as a major active component of turmeric attenuates proteinuria in patients with overt diabetic nephropathy. Full Text
Curcumin effects on myeloperoxidase, interleukin-18 and matrix metalloproteinase-9 inflammatory biomarkers in patients with unstable angina: A randomized clinical trial. Full Text
Potential of Curcumin in Skin Disorders Full Text
Synergistic Effects of Curcumin and Piperine as Potent Acetylcholine and Amyloidogenic Inhibitors With Significant Neuroprotective Activity in SH-SY5Y Cells via Computational Molecular Modeling and in vitro Assay. Full Text

Fisetin – a flavonoid found in highest concentration 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, a potential caloric restriction mimetic, modulates ionic homeostasis in senescence induced and naturally aged rats.
Fisetin improves lead-induced neuroinflammation, apoptosis and synaptic dysfunction in mice associated with the AMPK/SIRT1 and autophagy pathway.
Fisetin, a 3,7,3',4'-Tetrahydroxyflavone Inhibits the PI3K/Akt/mTOR and MAPK Pathways and Ameliorates Psoriasis Pathology in 2D and 3D Organotypic Human Inflammatory Skin Models. Full Text

Nicotinamide MonoNucleotide (NMN) – newer NAD+ precursor. I take 250 – 500mg on days I exercise.
Altered muscle electrical tissue properties in a mouse model of premature aging.

Nicotinamide Riboside (NR) – NAD+ precursor.
Nicotinamide riboside exerts protective effect against aging-induced NAFLD-like hepatic dysfunction in mice. Full Text
NAD+ precursor increases aerobic performance in mice.
Combined Treatment with L-Carnitine and Nicotinamide Riboside Improves Hepatic Metabolism and Attenuates Obesity and Liver Steatosis. Full Text

Pterostilbene – found in blueberries. Anti-oxidant, anti-inflamatory 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.

Resveratrol – found in the skin of grapes. Anti-oxidant, anti-inflamatory and Sir1 activator. Taking 250mg intermittently in the same pill as pterstilbene. Works better in conjunction with NAD+ precursors & Spermidine.
*The Effect of Resveratrol Supplementation on Cardio-Metabolic Risk Factors in Patients with Type 2 Diabetes: A Randomized, Double-Blind Controlled Trial.
*Resveratrol Treatment in Patients with Polycystic Ovary Syndrome Decreased Pro-inflammatory and Endoplasmic Reticulum Stress Markers.
*The effects of resveratrol on metabolic status in patients with type 2 diabetes mellitus and coronary heart disease.
*In vivo studies of resveratrol contained in cosmetic emulsions. Full Text
Resveratrol Activates Autophagy via the AKT/mTOR Signaling Pathway to Improve Cognitive Dysfunction in Rats With Chronic Cerebral Hypoperfusion. Full Text
Resveratrol improves cardiac function by promoting M2-like polarization of macrophages in mice with myocardial infarction. Full Text
The Impact of Resveratrol Supplementation on Inflammation Induced by Acute Exercise in Rats: Il6 Responses to Exercise. Full Text

Spermidine – found in wheat germ and a potent inducer of autophagy, it works in synergy with Resveratrol. I try to eat a few of teaspoons of wheat germ every day in my berry & nut breakfast.
Involvement of Spermidine in the Reduced Lifespan of Caenorhabditis elegans During Vitamin B12 Deficiency Full Text
Spermidine ameliorates liver ischaemia-reperfusion injury through the regulation of autophagy by the AMPK-mTOR-ULK1 signalling pathway. Full Text

Prescription Supplements

Metformin – First of all, a bit of a mea culpa on my part as I have so far ignored Metformin in these newsletters. If you have ever read any other articles about longevity, then will probably have read about this drug, which is the most commonly prescribed anti-diabetes medication in the world and has been touted as the world’s first anti-ageing drug. It also appears to be most common anti-ageing medicine used by longevity researchers. Why then have I ignored it? Because it failed to produce life-extension in the gold standard of ageing research – the Interventions Testing Program run by the NIA. It might still have beneficial effects, but it also requires a prescription. All year I have been in two minds about its costs/benefits, as witnessed by the unused cartons sitting in my fridge. See the articles below for further details as to why I am reticent.
Metformin and Aging: A Review. Full Text
Taming expectations of metformin as a treatment to extend healthspan Full Text
Metformin as Anti-Aging Therapy: Is It for Everyone?
*Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Full Text
*Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double-blind, placebo-controlled, multicenter trial: The MASTERS trial. Full Text
Peter Attia - Metformin and exercise – déjà vu all over again?
Age- and sex-dependent effects of metformin on neural precursor cells and cognitive recovery in a model of neonatal stroke Full Text

Rapamycin (sirolimus) – first drug proven to increase the health & lifespan of mice. Currently used for organ transplantation and against cancer. Was taking 5mg (or only 3.23mg?) once a week before my source’s legitimacy was questioned, stopped & have yet to resume.
Relationship Between mTOR Signaling Activation and Postoperative Neurocognitive Disorder in Aged Rats
Effects of autophagy on apoptosis of articular chondrocytes in adjuvant arthritis rats Full Text
Modulation of oxidative/nitrosative stress and inflammatory response by rapamycin in target and distant organs in rats exposed to hindlimb ischemia/reperfusion: The role of mTOR.
Rapamycin attenuates liver injury caused by vinyl chloride metabolite chloroethanol and lipopolysaccharide in mice.
*Low dose of IL-2 combined with rapamycin restores and maintains the long-term balance of Th17/Treg cells in refractory SLE patients. Full Text
Prevention of post-ischemic seizure by rapamycin is associated with deactivation of mTOR and ERK1/2 pathways in hyperglycemic rats.
Mitophagy protects against acetaminophen-induced acute liver injury in mice through inhibiting NLRP3 inflammasome activation.

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:
Stem Cell Senescence: The Obstacle of the Treatment of Degenerative Disk Disease.
The Heterogeneity of Senescent Cells
Senescent Cells Linked to Age-Related Blood Clot Formation Full Text
Microglia and the Aging Brain: Are Senescent Microglia the Key to Neurodegeneration? Full Text
Targeting senescence improves angiogenic potential of adipose-derived mesenchymal stem cells in patients with preeclampsia. Full Text
Src Tyrosine Kinase Inhibitors: New Perspectives on Their Immune, Antiviral, and Senotherapeutic Potential. Full Text

Epigenetic Cellular Reprogramming/Aging Clocks – the next big thing in longevity science as far as I am concerned & the closest thing we might have to a silver bullet against ageing. It involves targeting the epigenome:
Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells. Full Text
Primal health research in the age of epigenetic clocks Full Text

Young Blood Factors – 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:
Looking to Young Blood to Treat the Diseases of Aging Full Text

Odds & Sods

A NeuroD1 AAV-Based Gene Therapy for Functional Brain Repair after Ischemic Injury through In Vivo Astrocyte-to-Neuron Conversion Full Text
Effects of age-dependent changes in cell size on endothelial cell proliferation and senescence through YAP1 Full Text
Autologous Cell Therapy for Aged Human Skin: A Randomized, Placebo-Controlled, Phase-I Study.
Pyrroloquinoline quinone delays inflammaging induced by TNF-α through the p16/p21 and Jagged1 signalling pathways.
Royal Jelly and Its Components Promote Healthy Aging and Longevity: From Animal Models to Humans. Full Text
The Paradox of Coenzyme Q10 in Aging Full Text
Microbiome: Effects of Ageing and Diet. Full Text
Tendon stem/progenitor cell ageing: Modulation and rejuvenation. Full Text
Neuronal O-GlcNAcylation Improves Cognitive Function in the Aged Mouse Brain. Full Text
Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention Full Text
Testosterone therapy induces molecular programming augmenting physiological adaptations to resistance exercise in older men Full Text
The role of lipid metabolism in aging, lifespan regulation, and age-related disease Full Text
Lifelong choline supplementation ameliorates Alzheimer's disease pathology and associated cognitive deficits by attenuating microglia activation. Full Text
Maximizing Longevity and Healthspan: Multiple Approaches All Converging on Autophagy. Full Text