March 2019 Longevity Review

Hello and welcome once again to my longevity update, which I finally appear to be getting the hang of producing (though it’s still taking me 5 days of solid effort). Last month I showed you one potential “silver bullet” to combat ageing: young blood plasma. Now I want to show you another, once again before it has even been published: cellular re-programming.

In 2016 a landmark paper came out showing that it was possible to rejuvenate (to a degree) an entire animal by making all of its individual cells young again by re-programming their epigenome (Cellular reprogramming slows aging in mice Full Text). Science takes time, and since then I’ve been eagerly awaiting the follow-up studies.

Those studies are now starting to arrive as shown by the one below. Although it was only performed in human cells, it shows an improvement in technique compared to the study above.

Transient non-integrative nuclear reprogramming promotes multifaceted reversal of aging in human cells

And here is an interesting interview with a member of the above team: https://www.leafscie...no-of-turn-bio/

Here is another interview with a different company working in this area, demonstrating the breadth of this field: https://www.leafscie...th-yuri-deigin/

For a more general overview of this field, this article, by the same scientist featured in last month’s podcasts, is worth a read through:
LEAF overview: Epigenetic Alterations and Reprogramming Potential in AgingAbstract: Epigenetic changes during aging and their reprogramming potential. Full Text

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March Round-Up

In a similar vein to re-programming, this study shows a different method to get heart cells to behave younger so that they grow in number (heart cells don’t generally divide that much), which could be beneficial after heart attacks for example.
YAP Partially Reprograms Chromatin Accessibility to Directly Induce Adult Cardiogenesis In Vivo. Full Text

This study used gene editing to enhance a single gene (FOXO3) so that it improves the ability of stem cells to produce new blood vessels and to prevent them from turning cancerous.
FOXO3-Engineered Human ESC-Derived Vascular Cells Promote Vascular Protection and Regeneration. Full Text

In the January update I mentioned that Acarbose lengthened mouse lifespan as part of the NIA’s Interventions Testing Program. Normally there is quite a gap in releases, so I was quite surprised to see another one sneak in at the end of March. This time they found out that Glycine, but unfortunately not Aspirin or Inulin, extends the lifespan of mice by 4 to 6%.
Glycine supplementation extends lifespan of male and female mice

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In this month’s video/pod-cast, I want to draw your attention to a 20 minute presentation given by Jim Mellon, who is a very well respected billionaire investor. In the last few years he’s jumped into anti-ageing big time, investing millions into companies while at the same time claiming that this field will turn into the biggest “money fountain” the world has ever seen. He knows what he’s talking about as evidenced by his book Juvenescence, and in his talk he gives a whirlwind tour through the state of the field and why he is so optimistic. His enthusiasm is infectious! (PS – in the talk he also says that he is going to start taking Rapamycin after witnessing the effects it’s had on his dog!)
Jim Mellon – Abundance 360 Presentation:

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On a personal level, I’ve now upped my weekly Rapamycin dose to 3.75mg, which I will do four times before going to 5mg. So far I’ve not noticed anything apart from maybe making it easier to lose the bit of weight I was trying to. The important thing is no discernable side effects. My big news is that I’ve been granted the chance to volunteer at an anti-ageing conference in New York in July. I’m super excited about this, as it will allow me to meet some of the luminaries of the field and hear about the latest breakthroughs.

In the supplemental attachment, I’ve expanded the lifestyle and senolytic sections. I realise that it is probably a bit overwhelming at the moment, and I will try to improve that in future updates, but it is primarily to be used as a reference source if you want to dive deep into the rabbit hole. For those of you that do, the highlights include human trials with Curcumin & Resveratrol as well as a plethora of Rapamycin studies ranging from why it improves the quality of protein production to why it might prevent both Cancer & Alzheimer’s (making me feel all the better for taking it myself) and a gaggle of senescent cell studies showing just how important their removal will turn out to be for reversing ageing.

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!

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Further sources of information:
Fight Aging!
Life Extension Advocacy Foundation (LEAF)
Longecity (good forums where the self-experimenters reside!)
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
Lifespan.io (Tied together with LEAF, I have a recurring monthly donation)

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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.

The Influence of Meal Frequency and Timing on Health in Humans: The Role of Fasting. Full Text
Dietary Restriction Extends Lifespan through Metabolic Regulation of Innate Immunity. Full Text
Dietary Restrictions and Nutrition in the Prevention and Treatment of Cardiovascular Disease. Full Text

Diet – let food be thy medicine…

Mediterranean-Style Diet Improves Systolic Blood Pressure and Arterial Stiffness in Older Adults. Full Text
Increased Consumption of Virgin Olive Oil, Nuts, Legumes, Whole Grains, and Fish Promotes HDL Functions in Humans. Full Text
Essential oils and functional herbs for healthy aging. Full Text

Exercise – if you could bottle the benefits of exercise, it would be the biggest blockbuster drug of all time.

Ten years younger: Practice of chronic aerobic exercise improves attention and spatial memory functions in ageing. Full Text
Physical Activity Alleviates Cognitive Dysfunction of Alzheimer's Disease through Regulating the mTOR Signaling Pathway. Full Text
Which type of exercise keeps you young? Full Text

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, neuro-protective and skin-protective qualities. I take 4mg daily.
The first study shows how Astaxanthin can be used to keep your skin youthful, though I’ve not really noticed anything yet myself with four months usage.

Astaxanthin has Distinct Biological Effects to Prevent the Photoaging of the Skin Even by its Postirradiation Treatment. Full text
Astaxanthin ameliorates cardiomyocyte apoptosis after coronary microembolization by inhibiting oxidative stress via Nrf2/HO-1 pathway in rats.
Effects of palmitate and astaxanthin on cell viability and proinflammatory characteristics of mesenchymal stem cells. Full Text

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.

*The effects of Curcumin supplementation on high-sensitivity C-reactive protein, serum adiponectin, and lipid profile in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled trial. Full Text
*Pharmacokinetics, Pharmacodynamics, and PKPD Modeling of Curcumin in Regulating Antioxidant and Epigenetic Gene Expression in Healthy Human Volunteers. Full Text
*The effects of Curcumin supplementation on liver enzymes, lipid profile, glucose homeostasis, and hepatic steatosis and fibrosis in patients with non-alcoholic fatty liver disease. Full Text
Curcumin intervention for cognitive function in different types of people: A systematic review and meta-analysis.
The Role of Curcumin in the Modulation of Ageing. Full Text
Nutrition and Wound Healing: An Overview Focusing on the Beneficial Effects of Curcumin. Full Text
Curcumin: A Potent Protectant against Esophageal and Gastric Disorders. Full Text
Effects of Prolonged Dietary Curcumin Exposure on Skeletal Muscle Biochemical and Functional Responses of Aged Male Rats. Full Text
Curcumin and its Potential for Systemic Targeting of Inflamm-Aging and Metabolic Reprogramming in Cancer. Full Text
Curcumin ameliorates chronic renal failure in 5/6 nephrectomized rats by regulation of the mTOR/HIF-1α/VEGF signaling pathway. Full Text

Fisetin – a flavonoid found in highest concentration in strawberries. Senolytic, anti-inflammatory, neuro-protective & Sirt1 activator. I take 100mg daily.

Mitigative effects of the bioactive flavonol Fisetin on high-fat/high-sucrose induced nonalcoholic fatty liver disease in rats. Full text
Fisetin ameliorates oxidative stress, inflammation and apoptosis in diabetic cardiomyopathy. Full Text

Nicotinamide MonoNucleotide (NMN) – newer NAD+ precursor. I take 250mg daily.

Nicotinamide adenine dinucleotide emerges as a therapeutic target in aging and ischemic conditions. Full Text
Drugs targeting SIRT1, a new generation of therapeutics for osteoporosis and other bone related disorders? Full Text
Role of endothelial NAD+ deficiency in age-related vascular dysfunction. Full Text
Stabilizing ends of chromosomes could treat age-related disease
Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease. Full Text

Nicotinamide Riboside (NR) – NAD+ precursor.

The NAD-Booster Nicotinamide Riboside Potently Stimulates Hematopoiesis through Increased Mitochondrial Clearance. Full Text
NAD+ supplementation rejuvenates aged gut adult stem cells. Full Text
Nicotinamide riboside protects against liver fibrosis induced by CCl4 via regulating the acetylation of Smads signaling pathway. Full Text

Pterostilbene – found in blueberries. Anti-oxidant, anti-inflamatory and Sir1 activator. Similar to, but with greater bioavailability than resveratrol. Took some last year (50mg) and will order again. Works better in conjunction with NAD+ precursors.

Differential proteomic profiling identifies novel molecular targets of Pterostilbene against experimental diabetes. Full Text

Resveratrol – found in the skin of grapes. Anti-oxidant, anti-inflamatory and Sir1 activator. Took a low dose last year (50mg), will order again. Works better in conjunction with NAD+ precursors & Spermidine.

*Can Resveratrol supplement change inflammatory mediators? A systematic review and meta-analysis on randomized clinical trials. Full Text
*Resveratrol supplementation significantly influences obesity measures: a systematic review and dose-response meta-analysis of randomized controlled trials. Full Text
Resveratrol prevents the development of high blood pressure in spontaneously hypertensive rats through the inhibition of enhanced expression of Giα proteins.
Resveratrol attenuates metabolic, sperm, and testicular changes in adult Wistar rats fed a diet rich in lipids and simple carbohydrates. Full Text
Resveratrol prevents cognitive deficits by attenuating oxidative damage and inflammation in rat model of streptozotocin diabetes induced vascular dementia. Full Text
Systemic treatment with Resveratrol alleviates adjuvant arthritis-interstitial lung disease in rats via modulation of JAK/STAT/RANKL signaling pathway. Full Text

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.

Spermidine confers liver protection by enhancing NRF2 signaling through a MAP1S-mediated non-canonical mechanism. Full Text
Spermidine and Voluntary Activity Exert Differential Effects on Sucrose- Compared with Fat-Induced Systemic Changes in Male Mice. Full Text
Dietary and Gut Microbiota Polyamines in Obesity- and Age-Related Diseases. Full Text

Prescription Supplements

Rapamycin – first drug proven to increase the health & lifespan of mice. Currently used for organ transplantation and against cancer. Have taken four doses of 2.5mg and will now move up to 3.75mg.
The first study shows how Rapamycin improves the quality of protein production in our cells. The second is an interesting hypothesis on how Rapamycin might prevent both cancer and Alzheimer’s, while the third shows that Rapamycin might work in addition to dietary restriction as oppose to just replicating its results.

Regulation of the Elongation Phase of Protein Synthesis Enhances Translation Accuracy and Modulates Lifespan. Full Text
Alzheimer's Disease and Cancer: When Two Monsters Cannot Be Together. Full Text
Is Rapamycin a Dietary Restriction Mimetic? Full Text
Rapamycin Induced Autophagy Inhibits Inflammation-Mediated Endplate Degeneration by Enhancing Nrf2/Keap1 Signalling of Cartilage Endplate Stem Cells. Full Text
Differential Effects of Rapamycin and Metformin in Combination with Rapamycin on Mechanisms of Proteostasis in Cultured Skeletal Myotubes. Full text
Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential. Full Text
Rapamycin induced miR 30a downregulation inhibits senescence of VSMCs by targeting Beclin1. Full Text
Activation of mTORC1/PGC1 axis promotes mitochondrial biogenesis and induces cellular senescence in the lung epithelium. Full Text
Rapamycin Inhibited Photoreceptor Necroptosis and Protected the Retina by Activation of Autophagy in Experimental Retinal Detachment. Full Text
Rapamycin Removes Damaged Mitochondria and Protects Human Trabecular Meshwork (TM-1) Cells from Chronic Oxidative Stress (Glaucoma). Full Text
Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis. Full Text
mTORC1 underlies age-related muscle fiber damage and loss by inducing oxidative stress and catabolism. Full Text
Quantitative Systems Pharmacological Analysis of Drugs of Abuse Reveals the Pleiotropy of Their Targets and the Effector Role of mTORC1. 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:

Pharmacological clearance of senescent cells improves survival and recovery in aged mice following acute myocardial infarction. Full Text
Aged-senescent cells contribute to impaired heart regeneration. Full Text
Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Full Text
Senolytics and senostatics as adjuvant tumour therapy. Full Text
Systemic clearance of p16INK4a -positive senescent cells mitigates age-associated intervertebral disc degeneration. Full Text