August 2019 Longevity Review

August Longevity Update

Hello and welcome once again to this month’s longevity update. After an uber-busy summer work wise, I’m back to famine (such is the life of a contract teacher), but at least it means I can devote more time to longevity and get these newsletters sent out more promptly!

I’ve been asked by a few people how my longevity regimen is working out, and truth be told I have absolutely no idea! I have not noticed or felt anything, and the grey hairs on my beard have not magically reversed back to black. But, then again, I wasn’t expecting to as I already lead a fairly healthy lifestyle (daily fasting, healthy diet & plenty of movement), and haven’t yet felt the physical or mental effects of ageing. I have been taking some basic biomarkers (weight, blood pressure & blood glucose), so maybe once I get around to analyzing them some trend will emerge. Basically, I’m trusting in the science and hope that my regimen will provide benefit in the long term.

I had however hoped to pass on some anecdotal results via my parents, who being in their late seventies, could potentially see some noticeable results. Unfortunately, despite having all the necessary supplements & detailed instructions since June, they had not started yet (“once we’re back from holiday; once the patio is done; once etc etc…”). I finally lost it a couple of days ago and had to be quite brutal to them. I told my mom I wouldn’t speak to her again until she started and asked my dad how much he had enjoyed her stroke last year and if he was looking forward to the next one. He was quite understandably shocked, but it did the trick and they started that very same day! I will provide an anecdotal update in a few months time.

In the meantime, I’ve added a few sections to the end of the supplementary information, as there is so much exciting news out there and I didn’t want to clog up the round-up section. The new sections concern cellular reprogramming, young blood factors and miscellaneous, where you can find stuff on stem cells, ageing theories & how optimists live longer!

Follow me on Twitter @ChrisPollyanna1 for the latest updates! (after a two month hiatus… )

Finally – please feel free to forward this email to anyone who might be interested, and please let me know if anyone would like to be included in my mailing list! Also, any feedback is greatly appreciated… J
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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 have still 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.

August Round-Up:

• This exciting study is the first to try to recapitulate the benefits of young blood via the modulation of a couple of blood factors which change with age. Because ageing is a multi-factoral condition, scientists need to combine treatments, and the great thing about this study is that they do so. Also the two drugs used are already FDA approved, which means that translation to the clinic should be easier. Notwithstanding the additional benefit of not needing young blood in the first place! Rejuvenation of brain, liver and muscle by simultaneous pharmacological modulation of two signaling determinants, that change in opposite directions with age. Full Text

In the same vein (pardon the pun) the following announcement is from a company which uses a proprietary fraction of young blood plasma to try to treat age related conditions. The promising top-line results here are for Alzheimer’s (full results to be presented at a conference in December): Alkahest Announces Positive Top-line Data from Phase 2 Study in Mild to Moderate Alzheimer’s Disease

• Rather than looking at the benefits of young blood in an aged animal, the following study looked at young bone marrow (containing stem cells) transplanted into old mice and the effects on heart attack recovery. The results showed an improvement in recovery after an induced heart attack, as well as a reduction in cardiac senescent cell burden and a degree of rejuvenation: Long-term repopulation of aged bone marrow stem cells using young Sca-1 cells promotes aged heart rejuvenation. Full Text

• Fascinating article (I learnt a lot) about a class of drugs which can help ageing by preventing or reversing detrimental changes to the epigenome. If you are following a ketogenic diet or “keto” for short, then this might be the mechanism behind its health benefits, as keto bodies turn out to be HDAC inhibitors: From molecular promise to preclinical results: HDAC inhibitors in the race for healthy aging drugs. Full Text

• Another potential mechanism for improving longevity is to increase our telomeres (protective caps at the end of our chromosomes) via activating the enzyme telomerase. This paper looks at various nutrients which do so – main take away: olive oil is very good for you! Discovery of potent telomerase activators: Unfolding new therapeutic and anti-aging perspectives. Full Text

• For those of you lamenting the need for reading glasses, here is a phase I/II study of some eye drops which reverse the stiffening of the eye and improve near vision: Clinical Trial of a Cross-Link Breaker to Treat Presbyopia in the Aging Eye Treating presbyopia with an eye drop?

• Finally, the current issue of MIT Technology Review is devoted to longevity - Old Age Is Over! – if you want it with some very interesting articles (LEAF commentary). Unless you buy a copy or subscribe digitally, you are only allowed to access three articles per month. Here are my three recommendations:

Has this scientist finally found the fountain of youth?, about partial epigenetic reprogramming, the leading story from last month’s update.

The anti-aging drug that’s just around the corner, about the Rapamycin analogue mentioned last month (I can’t let a month go by without mentioning Rapamycin, can I?).

The transhumanists who want to live forever, about the biohackers taking matters into their own hands.

An eloquent polemic about ageing and what we should do about it by Reason, the author of the blog Fight Aging!, which I read on a daily basis (& whom I got to meet at the conference in July). The longevity field is roughly divided into two camps, those who think that it is programmed and those who think that it is the result of wear & tear damage. He is firmly in the damage camp. As a counterpoint, underneath is the programmed ageing view as espoused by Josh Mittledorf, another blogger I follow (& met as well), in relation to the cellular reprogramming study talked about last month.
YouTube link
Fight Aging! Link with transcript
Josh’s indirect response:
https://joshmitteldo...the-cell-level/
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Further sources of information:
Fight Aging! (run by the gentleman in the video above, 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)

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August 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.
*Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans. Full Text
*Recurrent circadian fasting (RCF) improves blood pressure, biomarkers of cardiometabolic risk and regulates inflammation in men. Full Text
Short-term dietary restriction in old mice rejuvenates the aging-induced structural imbalance of gut microbiota. Full Text
Comparison of glycemic improvement between intermittent calorie restriction and continuous calorie restriction in diabetic mice Full Text

Diet – let food be thy medicine…
*Health Benefits of Nut Consumption in Middle-Aged and Elderly Population Full Text
*Diet Quality Is Associated With Mortality in Adults Aged 80 Years and Older: A Prospective Study.
*Adherence to a Mediterranean diet is associated with cognitive function in an older non-Mediterranean sample: findings from the Maine-Syracuse Longitudinal Study.
*Coffee Consumption and Risk of Atrial Fibrillation in the Physicians' Health Study Full Text

Exercise – if you could bottle the benefits of exercise, it would be the biggest blockbuster drug of all time.
*Dose-response associations between accelerometry measured physical activity and sedentary time and all cause mortality: systematic review and harmonised meta-analysis. Full Text
*Isometric handgrip training reduces blood pressure and wave reflections in East Asian, non-medicated, middle-aged and older adults: a randomized control trial.

Non-prescription Supplements (in alphabetical order)

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 4mg daily.
Effects of astaxanthin onaxonal regeneration via cAMP/PKA signaling pathway in mice with focal cerebral infarction
Therapeutic and Protective Effects of Liposomal Encapsulation of Astaxanthin in Mice with Alcoholic Liver Fibrosis Full Text
Can krill oil be of use for counteracting neuroinflammatory processes induced by high fat diet and aging?

Curcumin – the spice which gives curries their yellow colour. Anti-inflammatory and neuroprotective. I take 1 gram a day. Needs to be taken with black pepper (piperine) to improve bio-availability.
Curcumin and Type 2 Diabetes Mellitus: Prevention and Treatment. Full Text
*Postprandial Responses of Serum Bile Acids in Healthy Humans after Ingestion of Turmeric before Medium/High-Fat Breakfasts
*The effects of curcumin supplementation on endothelial function: A systematic review and meta-analysis of randomized controlled trials.
The Autophagy Signaling Pathway: A Potential Multifunctional Therapeutic Target of Curcumin in Neurological and Neuromuscular Diseases. Full Text
*Curcumin for depression: a meta-analysis.
*Oral Curcumin No More Effective Than Placebo in Preventing Recurrence of Crohn's Disease After Surgery in a Randomized Controlled Trial.

Fisetin – a flavonoid found in highest concentration in strawberries. Senolytic, anti-inflammatory, anti-cancer, neuro-protective & Sirt1 activator. I take 100mg daily.
Fisetin Suppresses the Proliferation and Metastasis of Renal Cell Carcinoma through Upregulation of MEK/ERK-Targeting CTSS and ADAM9. Full Text

Nicotinamide MonoNucleotide (NMN) – newer NAD+ precursor. I take 250mg daily.
Impacts of obesity, maternal obesity and nicotinamide mononucleotide supplementation on sperm quality in mice Full Text
Corneal Denervation Causes Epithelial Apoptosis Through Inhibiting NAD+ Biosynthesis Full Text
Nicotinamide mononucleotide (NMN) supplementation promotes anti-aging miRNA expression profile in the aorta of aged mice, predicting epigenetic rejuvenation and anti-atherogenic effects.

Nicotinamide Riboside (NR) – NAD+ precursor.
*Effects of nicotinamide riboside on endocrine pancreatic function and incretin hormones in obese, non-diabetic men
*Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures. Full Text
Why Is Mom Stressed: Homeorhesis as the Potential Problem and Nicotinamide Riboside as the Potential Solution. Full Text
Supplementation with Nicotinamide Riboside Reduces Brain Inflammation and Improves Cognitive Function in Diabetic Mice. Full Text

Pterostilbene – found in blueberries. Anti-oxidant, anti-inflamatory and Sir1 activator. Similar to, but with greater bioavailability than resveratrol. Just started taking 50mg again daily. Works better in conjunction with NAD+ precursors.
Pterostilbene inhibits lung squamous cell carcinoma growth in vitro and in vivo by inducing S phase arrest and apoptosis. Full Text

Resveratrol – found in the skin of grapes. Anti-oxidant, anti-inflamatory and Sir1 activator. Just started taking 250mg a day. Works better in conjunction with NAD+ precursors & Spermidine.
*Acute resveratrol supplementation in coronary artery disease: towards patient stratification.
Effect of resveratrol on adipokines and myokines involved in fat browning: perspectives in healthy weight against obesity. Full Text
Resveratrol rescues tau-induced cognitive deficits and neuropathology in a mouse model of tauopathy.
Resveratrol prevents chronic intermittent hypoxia-induced cardiac hypertrophy by targeting the PI3K/AKT/mTOR pathway.

Spermidine – found in wheat germ and a potent inducer of autophagy, it works in synergy with Resveratrol. I try to eat a couple of tablespoons of wheat germ every day.
Polyamines Control eIF5A Hypusination, TFEB Translation, and Autophagy to Reverse B Cell Senescence Full Text

Prescription Supplements & Extra

Rapamycin (sirolimus) – first drug proven to increase the health & lifespan of mice. Currently used for organ transplantation and against cancer. Taking 5mg once a week.
Hypothalamic mTORC2 is essential for metabolic health and longevity. Full Text
Fasting and rapamycin: diabetes versus benevolent glucose intolerance. Full Text
Local intra-articular injection of rapamycin inhibits NLRP3 activity and prevents osteoarthritis in mouse DMM models.
Neuronal TORC1 modulates longevity via AMPK and cell nonautonomous regulation of mitochondrial dynamics in C. elegans. Full Text
Activation of mTORC1 in fibroblasts accelerates wound healing and induces fibrosis in mice.
Rapamycin protects aging muscle Full Text
Rapamycin attenuates Tc1 and Tc17 cell responses in cigarette smoke-induced emphysema in mice.
Rapamycin ameliorates immune-mediated aplastic anemia by inhibiting the proliferation and metabolism of T cells.
Regulation of YAP by Mammalian Target of Rapamycin Complex 1 in Endothelial Cells Controls Blood Pressure Through COX-2/mPGES-1/PGE2 Cascade

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:
Removing Dysfunctional Microglia Prevents Amyloid-β Plaques Full Text
Cellular senescence: at the nexus between ageing and diabetes. Full Text
Targeting p16-induced senescence prevents cigarette smoke-induced emphysema by promoting IGF1/Akt1 signaling in mice. Full Text
Targeting normal and cancer senescent cells as a strategy of senotherapy
Cortical neurons develop a senescence-like phenotype promoted by dysfunctional autophagy. Full Text
Mitochondrial metabolic reprograming via BRAF inhibition ameliorates senescence.

Epigenetic Cellular Reprogramming – 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:
Inducing Pluripotency Through Multiple Routes Full Text
Epigenetic Changes as a Target in Aging Haematopoietic Stem Cells and Age-Related Malignancies Full Text
Age-Related DNA Methylation Changes: Potential Impact on Skeletal Muscle Aging in Humans. Full Text
Screening for genes that accelerate the epigenetic aging clock in humans reveals a role for the H3K36 methyltransferase NSD1. Full Text
*Exploring Epigenetic Age in Response to Intensive Relaxing Training: A Pilot Study to Slow Down Biological Age 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:
*Soluble Intercellular Adhesion Molecule-1 (sICAM-1) as a Biomarker of Vascular Cognitive Impairment in Older Adults
Circulating factors in young blood as potential therapeutic agents for age-related neurodegenerative and neurovascular diseases
Young Blood Rescues the Cognition of Alzheimer's Model Mice by Restoring the Hippocampal Cholinergic Circuit.

Odds & Sods
A meta-analysis of genome-wide association studies identifies multiple longevity genes. Full Text
Vitamin K as a Powerful Micronutrient in Aging and Age-Related Diseases: Pros and Cons from Clinical Studies. Full Text
Optimism is associated with exceptional longevity in 2 epidemiologic cohorts of men and women.
Rejuvenating Strategies of Tissue-specific Stem Cells for Healthy Aging Full Text
Revamping the Evolutionary Theories of Aging Full Text
Toward a unified theory of aging and regeneration Full Text
Recent advances in understanding the mechanisms determining longevity. Full Text
Reducing Gut Dysbiosis Partially Alleviates Alzheimer’s Symptoms