2019 Longevity Year in Review

2019 Longevity Year in Review

When I sat down to write this year in review, I thought I had a pretty good handle on what had happened in the field of longevity in the last year. However, going through my newsletters, I was astonished by how much I had simply forgotten about. Therefore it was a real pleasure to revisit those past advances and discoveries, but at the same time it was difficult to pick out a top ten or anything like that. As a result I have grouped the advances into seven broad categories and created more of a narrative with the advances themselves embedded within. In the supplemental section, I have selected the 3/4 most important studies for each supplement, with precedence given to human results and those with access to the full text.

Hopefully this year end review will persuade you of the rapid progress being made against ageing and banish any thoughts that ageing will not in the near to medium term future be brought under control. I would also love to hear your opinions: Have I left any major advances out? Have I put too much emphasis on something? What do you think was the most important advance of 2019? Let me know in the comments section at the bottom!

As a reminder, you can follow me on Twitter @ChrisPollyanna1 and/or join my Facebook group Toronto Longevity Association

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1 Human Senolytic Results

By far the most important advances were the first tentative in-human senolytic results. As a refresher, senolytics is the clearance of senescent or “zombie cells”. These cells accumulate over time and cause immense harm as we age. Their clearance has led to some remarkable results in rodents. If even a fraction of the benefits translates to humans, then they will be a game changer. The first results came in Idiopathic Pulmonary Fibrosis, Osteoarthritis and Kidney Disease, and although the results were not earth shattering, these were primarily safety trials, so any indication of efficacy is extremely encouraging.

2 Other Human Trials

The most noteworthy and unexpected result involved a very small study rejuvenating the Thymus Gland (where our immune system matures) by the use of Human Growth Hormone, Metformin & DHEA. An unanticipated result was that the epigenetic age of the participants was reversed by 2.5 years! A much larger study which flew under the radar was a Phase IIa young blood plasma trial for Alzheimer’s, which seemed to slow or even stop deterioration. The significance of this doesn’t need emphasizing if born out in later trials. In smaller trials, stem cells were used for osteoarthritis, the combination of Fluvastatin & Valsartan (common medications for high cholesterol & blood pressure) was shown to upregulate longevity genes, Urolithin A ( a metabolite of pomegranate) improved mitochondrial health, and a cross-link breaker helped reduce Presbyopia (the need for reading glasses – hurray!). Finally, Rapamycin was shown to rejuvenate skin and decrease other medications needed for Rheumatoid Arthritis.

3 Novel Molecules or Procedures Showing Lifespan Extension in Rodents

I decided to exclude results from lower organisms, since there was an utter plethora of those studies and rodents are so much closer to us on an evolutionary scale. The gold standard in lifespan studies – the Interventions Testing Program, run by the NIA, showed that both Acarbose and Glycine extended life by up to 17% & 6% respectively. Two available supplements, Berberine & Alpha-Ketogluterate, did the same by up to 16% & 19%, though the later is only in pre-print. Moving from molecules, young bone marrow transplantation proved to be very effective with a 28% increased lifespan, and most interestingly Crispr-Cas9 (new fangled gene therapy) was used in this setting for the first time.

4 Combination Treatments in any Organism

Much more interesting than single interventions, which will only take us so far, is the combination of them, which will truly bring major progress and 2019 was certainly a banner year for that. It started out with some chemical compound pair synergies in yeast in January, followed in April by a new class of anti-HSP 90 molecules combined with Rapamycin in worms (along with a new method of finding novel lifespan drugs). However, it really kicked up a gear in August with the combo of Alk5i & Oxytocin in mice (coming from young blood research), which although was not a lifespan study, rejuvenated the brain, liver & muscles. This was continued by my personal highlight – the triple combination of Rapamycin (again), Lithium & Trametinib which in September showed a synergistic increase in the lifespan of fruit flies by 48%! Although the study was in flies it still showed the potential power of combinations targeting different longevity pathways. Then in November George Church brought us the first gene therapy combos, which although again were not aimed at lifespan, treated Type II Diabetes as well as heart & kidney failure.

5 Cellular Reprogramming

Even more exciting than combinations, which on the whole simply slow down ageing, is the very new field of cellular reprogramming, which has the potential to actually reverse ageing. There were only a few papers on this topic and two are only in pre-print, which means that they haven’t gone through the whole peer review process, but this field will explode in the coming years. January saw this process used to enhance tissue regeneration in mice; March introduced a new method rejuvenating old human cells; while April witnessed the application of the original method to rejuvenate old human stem cells. Meanwhile, in July, another new method from David Sinclair resulted in mice being able to re-grow their optic nerves, something hitherto impossible.

6 Young Factors

The transfer of youthful material (be it blood, plasma or other tissues) to older animals has produced some impressive positive results. The opposite has also occurred, with old blood causing harm. The race is now on to identify what is causing this and 2019 has produced a number of leads as well as further examples of this phenomenon. In January, MANF was discovered to protect against liver damage, while in April & May CD22 & VCAM1 respectively were shown to be detrimental. Also in May young plasma was again shown to be beneficial, while in February and August bone marrow & bone marrow stem cell transplants preserved cognition and rejuvenated hearts respectively. Finally, the transplanting of gut microbes in June reversed immune decline.

7 Honourable Mentions

A new epigenetic ageing clock was unveiled in January, from the author of the original ageing clock Steve Horvath, with the rather cute name GrimAge. It will purportedly tell you how long you have left to live, which will hopefully be rendered moot by longevity treatments, but will be useful in developing said treatments. The first instance of an Advanced Glycation End product (AGEs) breaker was shown in April. Think of AGEs as our bodies browning from the inside, which might be tasty on a steak, but we don’t want in our bodies! In September the field of drug development took a major step forward when AI was used to develop a new drug in less than 21 days, which is ridiculously quickly.

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Supplemental Section

***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 try to fast for at least 14 hours every day.
The Influence of Meal Frequency and Timing on Health in Humans: The Role of Fasting. Full Text
*Early Time-Restricted Feeding Improves 24-Hour Glucose Levels and Affects Markers of the Circadian Clock, Aging, and Autophagy in Humans. Full text
*The Effects of Time Restricted Feeding on Overweight, Older Adults: A Pilot Study Full Text
*Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans. 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
*A Mediterranean Diet with Fresh, Lean Pork Improves Processing Speed and Mood: Cognitive Findings from the MedPork Randomised Controlled Trial. Full Text
The Mediterranean Diet Slows Down the Progression of Aging and Helps to Prevent the Onset of Frailty: A Narrative Review. Full Text

Exercise – if you could bottle the benefits of exercise, it would be the biggest blockbuster drug of all time.
*Resistance Exercise Training as a Primary Countermeasure to Age-Related Chronic Disease Full Text
*Exercise Reverses Age‐Related Decline in NAD+ Salvage Capacity Full Text
*Effects of interval training on quality of life and cardiometabolic risk markers in older adults: a randomized controlled trial. Full Text
*Aerobic Exercise Training Improves Cerebral Blood Flow and Executive Function: A Randomized, Controlled Cross-Over Trial in Sedentary Older Men. 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 has Distinct Biological Effects to Prevent the Photoaging of the Skin Even by its Postirradiation Treatment. Full text
The Neuroprotective Effects of Astaxanthin: Therapeutic Targets and Clinical Perspective. Full Text
Astaxanthin Modulation of Signaling Pathways That Regulate Autophagy Full Text
Astaxanthin protects against osteoarthritis via Nrf2: a guardian of cartilage homeostasis. 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 Role of Curcumin in the Modulation of Ageing. Full Text
*The effect of curcumin supplementation on anthropometric indices, insulin resistance and oxidative stress in patients with type 2 diabetes: a randomized, double-blind clinical trial. Full Text
*A Highly Bioavailable Curcumin Extract Improves Neurocognitive Function and Mood in Healthy Older People: A 12-Week Randomised, Double-Blind, Placebo-Controlled Trial Full Text
Anti-inflammatory Action of Curcumin and Its Use in the Treatment of Lifestyle-related 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 and I’ve tried a couple of rounds of senolytic therapy at the same dosage as the clinical trials: 20mg/kg.
Nrf2⁻ARE Signaling Acts as Master Pathway for the Cellular Antioxidant Activity of Fisetin. Full Text
Phytomedicine-Based Potent Antioxidant, Fisetin Protects CNS-Insult LPS-Induced Oxidative Stress-Mediated Neurodegeneration and Memory Impairment. Full Text
Fisetin Alleviates Atrial Inflammation, Remodeling, and Vulnerability to Atrial Fibrillation after Myocardial Infarction. Full Text

Nicotinamide MonoNucleotide (NMN) – newer NAD+ precursor. I take 250 – 500mg on days I exercise.
NMN Enters Cells via Newly Discovered Pathway Full Text
Nicotinamide Mononucleotide: Exploration of Diverse Therapeutic Applications of a Potential Molecule. Full Text
Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Full Text
*Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men Full Text LEAF Review

Nicotinamide Riboside (NR) – another NAD+ precursor.
*Acute nicotinamide riboside supplementation improves redox homeostasis and exercise performance in old individuals: a double-blind cross-over study. Full Text
*Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults Full Text
*Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures. Full Text
*Effects of Nicotinamide Riboside on Endocrine Pancreatic Function and Incretin Hormones in Nondiabetic Men With Obesity.

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, a bioactive component of blueberries, alleviates renal fibrosis in a severe mouse model of hyperuricemic nephropathy. Full Text
Pterostilbene Improves Cognitive Performance in Aged Rats: An in Vivo Study. Full Text
Pterostilbene Attenuates Astrocytic Inflammation and Neuronal Oxidative Injury After Ischemia-Reperfusion by Inhibiting NF-κB Phosphorylation. Full Text
Pterostilbene reduces endothelial cell injury in vascular arterial walls by regulating the Nrf2-mediated AMPK/STAT3 pathway in an atherosclerosis rat model Full Text

Resveratrol – found in the skin of grapes. Anti-oxidant, anti-inflamatory and Sir1 activator. Taking 250mg intermittently in the same pill as pterostilbene. Works better in conjunction with NAD+ precursors & Spermidine.
*Effect of resveratrol supplementation on lipid profile in subjects with dyslipidemia: A randomized double-blind, placebo-controlled trial.
*The Effects of Resveratrol in Patients with Cardiovascular Disease and Heart Failure: A Narrative Review. Full Text
*Post-Exercise Recovery Following 30-Day Supplementation of Trans-Resveratrol and Polyphenol-Enriched Extracts. Full Text
*Higher dose of resveratrol elevated cardiovascular disease risk biomarker levels in overweight older adults - A pilot study.

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.
Spermidine: a physiological autophagy inducer acting as an anti-aging vitamin in humans? Full Text
Polyamines Control eIF5A Hypusination, TFEB Translation, and Autophagy to Reverse B Cell Senescence Full Text
Spermidine ameliorates liver ischaemia-reperfusion injury through the regulation of autophagy by the AMPK-mTOR-ULK1 signalling pathway. Full Text
Spermidine protects from age-related synaptic alterations at hippocampal mossy fiber-CA3 synapses. 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 (see September’s newsletter when I started following Metformin).
*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
Metformin Restores CNS Remyelination Capacity by Rejuvenating Aged Stem Cells. Full Text
*Metformin increases fasting glucose clearance and endogenous glucose production in non-diabetic individuals 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 and stopped. Got hold of legitimate Rapamycin to give to my mother, who is in the middle of a seven week course.
Rapamycin: A Bacteria-Derived Immunosuppressant That Has Anti-atherosclerotic Effects and Its Clinical Application. Full Text
Measuring biological age in mice using differential mass spectrometry. Full Text
Partial inhibition of mTORC1 in aged rats counteracts the decline in muscle mass and reverses molecular signaling associated with sarcopenia. Full Text
*Oral and Topical Sirolimus for Vascular Anomalies: a Multicentre Study and Review. Full Text
Rapamycin for longevity: opinion article. Full Text

Senolytics – not supplements or available now, but the most exciting area of anti-research at the moment.
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
Targeting senescent cells in translational medicine Full Text

PS - If you're wondering what happened to the other sections, apart from Metformin, I've only reviewed those sections which I've covered for the entire year.