January 2020 Longevity Review

January 2020 Longevity Review

Hello and welcome to the first Longevity Review of the new decade, which promises to be the decade when longevity science transitions from the laboratory & mice to the clinic & humans. By the end of this decade I fully expect the longevity field to have gone mainstream, with initial treatments available on a population scale in the most forward thinking countries with universal healthcare. Meanwhile in the lab, I would be very surprised if we are not by then seeing true full rejuvenation of old mice. And to cap it off, those in the know (ie you!), will be able to take advantage of the coming breakthroughs well before the general population.

Personally, after an indulgent festive period, I decided to go hardcore healthy for two weeks as I had my annual check-up at the end of the month and wanted to crush my blood markers. I was curious to see if trying to be perfectly healthy would make a difference, or whether sod’s law would raise its head and derail my ambitions. I also wanted to see if I could further improve my bio-age according to a spreadsheet based on the PhenoAge Clock. According to my last blood work in November 2018 I was 6.16 years younger than my chronological age, which was an improvement from the 1.58 years in 2017 when I was coming to the end of the most stressful period of my life. However, I had not yet started taking any of my supplements – would the ridiculous amount pills I take each week make a difference?

As it turns out, and to my pleasant surprise, maybe they did as my new bio-age is now 11.98 years younger than my actual age! Now I don’t take it at all seriously as there are too many unknowns (how much is due to pills, sleep, diet, exercise, random chance?) and the spreadsheet has not in any way been validated, but it may at least indicate a general health trend. Here's a link to download the spreadsheet for your amusement ( http://www.nickenger...henoAge_gen.xls ), but please, please, please do not take any actions based on the results. See your doctor for any interpretation and recommendations. Also, I should note that four of my blood markers not measured by the spreadsheet were outside the normal range (low – WBC, RBC & Neutrophils; high – urate), which I need to investigate further and they will be re-checked in a month’s time.

What are your thoughts about this PhenoAge Clock spreadsheet - just a gimmick or could there be some truth in it? Please comment at the bottom.

Follow me on Twitter @ChrisPollyanna1 for the latest updates.

And feel free to join my Toronto Longevity Association Facebook Group.

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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.

January Round-Up:

Maybe it was because of the time of year, but there seemed to be a lot of lifestyle studies dealing with diet and exercise or general healthy living, such as one showing that having five healthy habits at 50 could give you up to an extra decade.

Concerning diet, the Mediterranean diet seemed to come out best in terms of weight loss & health improvement, closely followed by the 5:2 fasting diet (where you severely restrict calories 2 days a week): Weight loss and health improvements with Mediterranean, fasting & Paleo diets

A further study on the Mediterranean diet seemed to show epigenetic improvement in a population not used to eating in that style: One-year Mediterranean diet promotes epigenetic rejuvenation with country- and sex-specific effects: a pilot study from the NU-AGE project. Full Text

And continuing with diet, the first small study on 16:8 fasting (fast for 16 hours a day & then eat however much you want in the remaining 8) in healthy non-obese adults, showed that it was safe & saw small health improvements over its six week duration: Short-term time-restricted feeding is safe and feasible in non-obese healthy midlife and older adults.

Moving onto exercise, training for your first marathon can take four years off of the age of your arteries: Training for a First-Time Marathon Reverses Age-Related Aortic Stiffening. Want to turn back time? Try running a marathon

But if that seems like a bridge too far, another studied showed that doing a mere 60 seconds of high Intensity Interval Training (HIIT) a week could lead to health improvements! The Impact of Sprint Interval Training Frequency on Blood Glucose Control and Physical Function of Older Adults Full Text

On a more theoretical bent, a study showed that people can be grouped into different Ageotypes according to how they age, which might make it easier in the future to come up with more personalized anti-ageing strategies: Your Ageotype Shows How You Age Personal aging markers and ageotypes revealed by deep longitudinal profiling

Finally, the winner for the most brazen headline goes to a study which elucidated the mechanisms by which two interventions synergistically lengthened worm life spans by 500%! And if it works for worms, surely it will eventually work for us, right? ;-) Pathways that extend lifespan by 500 percent identified Full Text

PS – there are some interesting senolytic animal studies in Senolytic section below.
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Video to watch:
File this under don’t do this at home or extreme bio-hacking, but Liz Parrish had herself injected with two gene therapies a few years ago – one to increase her telomeres and the other to increase her muscles. Pioneering or just plain crazy? You decide! From a presentation at the Church of Perpetual Life (I kid you not) about her experience & new gene therapy venture:
https://youtu.be/17KueSj26VM?t=200
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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)
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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January 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.*
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Lifestyle

Diet – let food be thy medicine…
*Effect of a 2-year diet intervention with walnuts on cognitive decline: The Walnuts And Healthy Aging (WAHA) study: a randomized controlled trial.
High-protein diets boost artery-clogging plaque, mouse study shows
Keto diet works best in small doses, mouse study finds
Theanine, the Main Amino Acid in Tea, Prevents Stress-Induced Brain Atrophy by Modifying Early Stress Responses. Full Text

Exercise – if you could bottle the benefits of exercise, it would be the biggest blockbuster drug of all time.
*Whey protein but not collagen peptides stimulate acute and longer-term muscle protein synthesis with and without resistance exercise in healthy older women: a randomized controlled trial.
*A High-Intensity Exercise Intervention Improves Older Women Lumbar Spine and Distal Tibia Bone Microstructure and Function: A 20-Week 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.
Combining antioxidant astaxantin and cholinesterase inhibitor huperzine A boosts neuroprotection. Full Text
Effect of astaxanthin on metabolic cataract in rats with type 1 diabetes mellitus
Protective Effects of Astaxanthin Supplementation against Ultraviolet-Induced Photoaging in Hairless Mice Full Text
Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway. Full Text
Haematococcus pluvialis-Derived Astaxanthin Is a Potential Neuroprotective Agent against Optic Nerve Ischemia. 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.
*The effects of curcumin supplementation on oxidative stress, Sirtuin-1 and peroxisome proliferator activated receptor γ coactivator 1α gene expression in polycystic ovarian syndrome (PCOS) patients: A randomized placebo-controlled clinical trial.
*The effects of curcumin supplementation on liver function, metabolic profile and body composition in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis of randomized controlled trials. Full Text
Efficacy of Curcumin on Aortic Atherosclerosis: A Systematic Review and Meta-Analysis in Mouse Studies and Insights into Possible Mechanisms. Full Text
Interference with AGEs formation and AGEs-induced vascular injury mediates curcumin vascular protection in metabolic syndrome. Full Text
Curcumin as a Therapeutic Option in Retinal Diseases Full Text

Fisetin – a flavonoid found in highest concentration in strawberries. Senolytic, anti-inflammatory, anti-cancer, neuro-protective & Sirt1 activator. I take 100mg intermittently.
Fisetin Improved Rotenone-Induced Behavioral Deficits, Oxidative Changes, and Mitochondrial Dysfunctions in Rat Model of Parkinson's Disease.

Nicotinamide MonoNucleotide (NMN) – newer NAD+ precursor. I take 250 – 500mg on days I exercise.
NAD+ therapy in age-related degenerative disorders: A benefit/risk analysis.
Extracellular NAD+ enhances PARP-dependent DNA repair capacity independently of CD73 activity. Full Text

Nicotinamide Riboside (NR) – NAD+ precursor.
Nicotinamide Riboside Enhances Mitochondrial Proteostasis and Adult Neurogenesis through Activation of Mitochondrial Unfolded Protein Response Signaling in the Brain of ALS SOD1G93A Mice. Full Text
Short-term NAD+ supplementation prevents hearing loss in mouse models of Cockayne syndrome. Full Text
Nicotinamide riboside rescues angiotensin II-induced cerebral small vessel disease in mice. Full Text
Targeting mitochondria to stimulate hematopoiesis Full Text
Evaluation of the NAD+ biosynthetic pathway in ALS patients and effect of modulating NAD+ levels in hSOD1-linked ALS mouse models. 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.
Pterostilbene Enhances Endurance Capacity via Promoting Skeletal Muscle Adaptations to Exercise Training in Rats. Full Text
Pterostilbene Improves Hepatic Lipid Accumulation via the MiR-34a/Sirt1/SREBP-1 Pathway in Fructose-Fed Rats.
Pterostilbene Suppresses both Cancer Cells and Cancer Stem-Like Cells in Cervical Cancer with Superior Bioavailability to Resveratrol.
Pterostilbene Inhibits Human Renal Cell Carcinoma Cells Growth and Induces DNA Damage. Full Text

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.
*Efficacy and Safety of Resveratrol in Type 1 Diabetes Patients: A Two-Month Preliminary Exploratory Trial. Full Text
*Resveratrol and metabolic health in COPD: A proof-of-concept randomized controlled trial.
Resveratrol promotes white adipocytes browning and improves metabolic disorders in Sirt1-dependent manner in mice. Full Text
Insights on the Effects of Resveratrol and Some of Its Derivatives in Cancer and Autoimmunity: A Molecule with a Dual Activity. Full Text
Resveratrol and the Interaction between Gut Microbiota and Arterial Remodelling 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.
*Prevention of Atherosclerosis by the Induction of Microbial Polyamine Production in the Intestinal Lumen Full Text
Spermidine alleviates cardiac aging by improving mitochondrial biogenesis and function. Full Text
Spermidine Exhibits Protective Effects Against Traumatic Brain Injury.
Spermidine Suppresses Inflammatory DC Function by Activating the FOXO3 Pathway and Counteracts Autoimmunity. Full Text

Other available supplements
α-Ketoglutarate Modulates Macrophage Polarization Through Regulation of PPARγ Transcription and mTORC1/p70S6K Pathway to Ameliorate ALI/ARDS.
Sirtuin 3 Activation by Honokiol Decreases Unilateral Ureteral Obstruction-Induced Renal Inflammation and Fibrosis via Regulation of Mitochondrial Dynamics and the Renal NF-κBTGF-β1/Smad Signaling Pathway. Full Text
Vitamin K as a Diet Supplement with Impact in Human Health: Current Evidence in Age-Related Diseases. Full Text
Impact of Melatonin on Skeletal Muscle and Exercise Full Text
Melatonin ameliorates the advanced maternal age-associated meiotic defects in oocytes through the SIRT2-dependent H4K16 deacetylation pathway. Full Text
Melatonin suppresses senescence-derived mitochondrial dysfunction in mesenchymal stem cells via the HSPA1L-mitophagy pathway. Full Text
Melatonin alleviates vascular calcification and ageing through exosomal miR-204/miR-211 cluster in a paracrine manner. Full Text
Quercetin-induced apoptosis ameliorates vascular smooth muscle cell senescence through AMP-activated protein kinase signaling pathway. Full Text
New Insights into the Biological and Pharmaceutical Properties of Royal Jelly Full Text
Riboflavin: The Health Benefits of a Forgotten Natural Vitamin. 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 use is associated with a lower risk of osteoporosis in adult women independent of type 2 diabetes mellitus and obesity. REDLINC IX study
Metformin Suppresses LPS-Induced Inflammatory Responses in Macrophage and Ameliorates Allergic Contact Dermatitis in Mice via Autophagy. Full Text
Metformin mediates cardioprotection against aging-induced ischemic necroptosis. Full Text
Metformin attenuates cartilage degeneration in an experimental osteoarthritis model by regulating AMPK/mTOR. Full Text
Metformin attenuates the D‑galactose‑induced aging process via the UPR through the AMPK/ERK1/2 signaling pathways. Full Text

Rapamycin (sirolimus) – first drug proven to increase the health & lifespan of mice. Currently used for organ transplantation and against cancer.
*Treatment of superficial vascular anomalies with topical sirolimus: A multicenter case series.
*Topical sirolimus for the treatment of cutaneous manifestations of vascular anomalies: A case series.
Inhibition of the mammalian target or rapamycin (mTOR): a potential therapeutic strategy for multiple system atrophy Full Text
Autophagy decreases alveolar epithelial cell injury by regulating the release of inflammatory mediators.
Sestrin prevents atrophy of disused and aging muscles by integrating anabolic and catabolic signals. Full Text
mTOR at the nexus of nutrition, growth, ageing and disease.

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:
Dasatinib plus quercetin prevents uterine age-related dysfunction and fibrosis in mice. Full Text
Cellular senescence contributes to age-dependent changes in circulating extracellular vesicle cargo and function. Full Text Dasatinib & Quercetin
Pharmacological or genetic depletion of senescent astrocytes prevents whole brain irradiation-induced impairment of neurovascular coupling responses protecting cognitive function in mice. Navitoclax
FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice. Full Text
A secreted signature of aging cells A proteomic atlas of senescence-associated secretomes for aging biomarker development

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:
*Exceptionally Long-Lived Individuals (ELLI) Demonstrate Slower Aging Rate Calculated by DNA Methylation Clocks as Possible Modulators for Healthy Longevity. Full Text
A proteomic atlas of senescence-associated secretomes for aging biomarker development Full Text
Dysfunctional epigenetic aging of the normal colon and colorectal cancer risk 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.
*Aerobic capacity and telomere length in human skeletal muscle and leukocytes across the lifespan Full Text
*Association between leucocyte telomere length and cardiovascular disease in a large general population in the United States Full Text
*The association of telomere length and telomerase activity with adverse outcomes in older patients with non-ST-elevation acute coronary syndrome Full Text
*Relative Telomere Length and Mitochondrial DNA Copy Number Variation with Age: Association with Plasma Folate and Vitamin B12.
*The effects of short-term combined exercise training on telomere length in obese women: a prospective, interventional study. Full Text

Stem Cells & Exosomes
Endothelial progenitor cells promote viability and nerve regenerative ability of mesenchymal stem cells through PDGF-BB/PDGFR-β signaling. Full Text
Tissue-infiltrating macrophages mediate an exosome-based metabolic reprogramming upon DNA damage. Full Text
Gene co-expression network for analysis of plasma exosomal miRNAs in the elderly as markers of aging and cognitive decline Full Text
Derivation of Cell-Engineered Nanovesicles from Human Induced Pluripotent Stem Cells and Their Protective Effect on the Senescence of Dermal Fibroblasts. Full Text

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:
Transplanting cells from old but not young donors causes physical dysfunction in older recipients. Full Text

Reviews
Contributions of Age-Related Thymic Involution to Immunosenescence and Inflammaging Full Text
Revisiting the Hallmarks of Aging to Identify Markers of Biological Age Full Text
Applications of genome editing technology in the targeted therapy of human diseases: mechanisms, advances and prospects. Full Text

Odds & Sods
*Waist-to-Height Ratio Outperforms Classic Anthropometric Indices in Predicting Successful Aging in Older Adults; an Analysis of the ATTICA and MEDIS Epidemiological Studies.
Tiny salamander's huge genome may harbor the secrets of regeneration Multiplex CRISPR/Cas screen in regenerating haploid limbs of chimeric Axolotls
Negligible senescence in naked mole rats may be a consequence of well-maintained splicing regulation. Full Text
Acarbose improved survival for Apc+/Min mice. Full Text
Protecting the Aging Genome Full Text
7-Ketocholesterol in disease and aging Full Text
Are Advances in Survival among the Oldest Old Seen across the Spectrum of Health and Functioning?
Deletion of Nrf2 shortens lifespan in C57BL6/J male mice but does not alter the health and survival benefits of caloric restriction.
Associations Between Declining Physical and Cognitive Functions in the Lothian Birth Cohort 1936. Full Text
The effects of bariatric surgery on clinical profile, DNA methylation, and ageing in severely obese patients Full Text
Aberrantly High Levels of Somatic LINE-1 Expression and Retrotransposition in Human Neurological Disorders Full Text
Dill Extract Induces Elastic Fiber Neosynthesis and Functional Improvement in the Ascending Aorta of Aged Mice with Reversal of Age-Dependent Cardiac Hypertrophy and Involvement of Lysyl Oxidase-Like-1. Full Text
Identification of 12 genetic loci associated with human healthspan Full Text