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Hacking aging - Part 2
This is the second part of the series on anti-ageing. In this article we will examine some promising approaches to hacking ageing, backed by scientific research, including fasting and various supplements.
This is the second part of the series on anti-aging. In this article we will examine some promising approaches to hacking aging, backed by scientific research, including fasting and various supplements.
Fasting
What is fasting and does it work?
Fasting is going without food, or consuming a calorie restricted diet for an extended period of time, some fasts are as short as 16 hours, some can be months long.
Fasting is probably one of the most extensively researched and evidence backed approaches for longevity. Strong evidence exists that restricting calories increases lifespan in mice and humans.
Fasting need not be constant, instead fasting for periods of time at regular intervals is sufficient to generate the same benefits seen in long term fasting studies. Interestingly rather than going without food completely similar results to fasting were observed using a Fasting Mimicking Diet (FMD), that is a diet low in calories, sugars, and proteins but high in unsaturated fats (1), one such popular diet is the Keto diet.
How does it work?
When fasting the body no longer has enough carbohydrates to sustain it and therefore switches to autophagy for its energy source. Autophagy literally translated from greek means “to eat oneself”.
The body feeds on the various damaged parts of cells such as cell membranes and proteins, thereby removing them from the body. When these sub-cellular parts are removed they are replaced with new parts, thereby restoring the cells to proper function.
In addition to promoting autophagy fasting also promotes the production of growth hormone, which helps the body produce these new replacement parts (2).
What are the benefits?
One study compared people who consumed a fasting mimicking diet for 5 days once a month for 3 months to those following a regular diet. Those who followed the periodic fasting diet showed reduced body weight and fat, lower blood pressure, and decreased IGF-1 hormone. IGF-1 has been linked to aging and disease. Further studies showed the fasting diet also decreased cholesterol and markers for inflammation (3). Animal studies have demonstrated a range of benefits including wound healing (4), and brain function (5).
How can I implement fasting in my daily life?
There are a number of ways to fast, some common approaches include:
16:8 fast: This involves limiting consumption to an 8 hour window per day. This cycle can be practiced as often as you like, once, twice per week or every day. An example of this would be skipping breakfast, but having a healthy lunch and dinner.
24 hour fast: This involves skipping meals for 24 hours, e.g. if your last meal is dinner you do not eat again until dinner the following night. This type of fast is more difficult and therefore not practiced as often, some people choose to do this once a week or once a month.
5:2 fast: This involves eating regularly for 5 days a week and eating a calorie restricted diet (no more than 500 calories per day) for 2 days a week.
Similar results can be achieved by following a calorie restricted diet such as the Keto diet. More information on the Keto diet can be found here.
Calorie Restriction Mimetics (CRM)
Let’s face it, fasting sucks, it is difficult for most people to maintain a fasted state, or even maintain intermittent fasting over a long period, therefore scientists have been researching Calorie Restriction Mimetics (CRM’s).
CRM’s are compounds when ingested mimic the body’s response to being in a fasted state. One promising group of CRM’s are sirtuin activators.
What sirtuans and sirtuan activators?
Sirtuans are proteins in the body which are responsible for DNA maintenance and repair. These genes are activated when the body senses it is in a stressed state (e.g. fasting). One of the seven sirtuans found in humans, SIRT1, can be activated by natural compounds known as polyphenols. Polyphenols are found in plants, where they are involved in defending plants from ultraviolet radiation and pathogens. Polyphenols include pterostilbene which is found in blueberries, resveratrol which is found in the skin of grapes and curcumin.
What else is required for sirtuan activators to work?
Sirtuans can only function in the presence of nicotinamide adenine dinucleotide (NAD+), NAD+ is a coenzyme found in all cells, it is responsible for helping turn nutrients into energy and regulating other biological activity. NAD+ levels in humans decline with age. Therefore boosting levels of NAD+ can help Sirtuans to continue functioning into old age.
Do these supplements work and can they by purchased?
Recent studies have highlighted potential positive effects from increased NAD+. One study showed that mice supplemented with NAD+ precursers showed increased levels of DNA repair and the tissues of 2 year old mice appeared identical to that of 3 month old mice (6). Another study showed increased levels of cognitive ability (7). There are not yet any results from human trials.
NAD+ can be taken directly or NAD+ levels can be increased by supplementation with the NAD+ precursors Nicotinamide Riboside (NR) or Nicotinamide Mononucleotide (NMN), both have been shown to raise the levels of NAD+ in the body. NR and NMN are derived from nicacin which is a form of vitamin B3, an essential human nutrient.
Most of these supplements can be purchased online, but beware are a lot of inferior products, and many which are not what the claim to be. Make sure you go with a reputable brand.
Senolytics
What are senescent cells?
As we age the body accumulates an increasing number of senescent cells. Sensescent cells are cells which are not functioning properly, but have not yet died off and been recycled, as cells are when we are younger.
Senescent cells secrete inflammatory factors, and appear to play a role an important role in ageing and many age related diseases including dementia, diabetes and cardiovascular disease (8).
Do senolytics work, and where can I purchase them?
The class of drugs known as senolytics target senescent cells, removing them but leaving healthy cells untouched. In various mice studies it has been shown that removal of senescent cells can prevent or delay tissue dysfunction and extend healthy lifespan (9, 10).
Many plant based compounds have powerful senolytic effects, one study compared the senolytic efficacy of various plant compounds in mouse cells and in senescent human fibroblasts, the results can be seen in the chart below (11).
Mouse embryonic fibroblasts (MEFs) were treated with a panel of flavonoid compounds, and the the viability of senescent cells and total cells were measured.
Among the 10 flavonoids tested Fisetin was the most effective. Fisetin is a natural compound found in strawberries, apples, cucumbers, grapes and onions. There are only a very few suppliers online, more common is curcumin, which can easily be purchased, fresh or in pill form. The bioavailabiliy of pure curcumin is relatively low, however taking it with piperine has been shown to increase its bioavailablity by as much as 2000%.
Metformin
No longevity discussion would be complete without mentioning Metformin. Metformin is a drug used to treat diabetes. When administered it mimics caloric restriction and therefore has also been shown to extend lifespan. The exact mechanism by which metformin works to increase lifespan is not yet fully understood. It appears to operate on a number of pathways including decreasing IGF-1, inhibition of mTOR, reducing DNA damage, and influencing inflammation and autophagy and influencing digestion in the gut microbiome (12).
Studies have demonstrated Metformin’s ability to increase lifespan in mice (13, 14). Several studies have shown metformin may be beneficial for decreasing the incidence of cancer, improving cognitive function and increasing lifespan (15, 16, 17). More targeted studies in humans are currently being conducted.
Metformin can in most countries be purchased with a doctor’s prescription.
Stacking for increased benefits
Evolve Fitness recommends stacking a sirtuan activator (e.g. resveratrol) an NAD+ precurser (such as NMN or NR) and a senolytic (curcumin), these can safely be taken on a daily basis however we recommend periodically taking a break from all supplement regimes. If you are considering taking metformin for longevity purposes we recommend you speak with your doctor first.
References
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4509734/
2. https://www.nobelprize.org/prizes/medicine/2016/press-release/
3. http://stm.sciencemag.org/content/9/377/eaai8700
4. https://www.ncbi.nlm.nih.gov/m/pubmed/25881054/
5. https://medium.com/lifeomic/this-is-your-brain-on-fasting-a77d9d264de7
6. http://science.sciencemag.org/content/355/6331/1312
7. https://www.ncbi.nlm.nih.gov/pubmed/29432159
8. https://www.ncbi.nlm.nih.gov/pubmed/26485647/
9. https://www.ncbi.nlm.nih.gov/pubmed/22048312/
10. https://www.ncbi.nlm.nih.gov/pubmed/26840489/
11. https://www.ebiomedicine.com/article/S2352-3964(18)30373-6/fulltext
12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943638/
13. https://www.ncbi.nlm.nih.gov/pubmed/18728386
14. https://www.ncbi.nlm.nih.gov/pubmed/21386129
15. https://www.ncbi.nlm.nih.gov/pubmed/24985407/
Hacking aging - Part 1 Could you live to 150?
If you could take a pill that allowed you to live to 150 would you? Would the answer change if you could spend those years looking and feeling fit, young, healthy and disease free? Believe it or not science may be very close to making this possible.
If you could take a pill that allowed you to live to 150 would you? Would the answer change if you could spend those years looking and feeling fit, young, healthy and disease free?
Believe it or not science may be very close to making this possible. In this article we will discuss some of the most promising recent discoveries in anti-aging research and which of these are already available.
What is longevity or anti-aging really about?
Modern medicine has become very good at repairing many of our organs, and keeping our hearts and lungs functioning. However often our brains and muscles fail us and we spend a considerable portion of the end of our lives in suffering.
Longevity isn’t about just about living longer, it is about living better and spending less of our lives in a diseased or frail state.
The biggest driver of disease is aging. In fact, age is the biggest risk factor for lung cancer, many times more important than smoking! Age is a key risk factor in many diseases including cancer, heart disease and diabetes.
If we could wind back the body clock, we would greatly reduce the risk of all these diseases, and be able to lead fitter, healthier lives. David Sinclair, who leads Harvard’s anti-aging research would go one step further to say aging itself is a disease, and one that is curable.
Anti-aging is a relatively new and exciting area of study, most of the studies to date have been on yeast and mice however the results are promising. Scientists have already been able to significantly slow and even reverse aging in the lab in yeast, mice and monkeys. Human trials are also beginning.
In the first part of this two-part series we will discuss the recent anti-aging discoveries in blood borne factors.
Can young blood make you younger?
Credit: Villeda lab
In 2005, scientists at Stanford conducted a gruesome experiment whereby they surgically attached an older mouse to a younger mouse, so that they shared one blood supply. What they observed was this improved the ability for the old mouse to heal and regenerate, effectively making the old mouse appear younger again.
It is believed that somehow the blood from the younger mouse caused the stem cells from the older mouse to become more effective at repairing damaged cells and tissue in the older mouse.
This discovery led to some silicon valley start ups offering older patients blood plasma infusions from younger donors! However in February 2019 the FDA announced such services would require Investigational New Drug approval - this effectively put these companies out of service for the time being.
The Young Blood Institute is currently conducting a large scale trial of blood transfusions (rather than infusions). In a transfusion they replace aged plasma in older subjects with young plasma components form younger subjects. Blood transfusions are considered safer than infusions, as the total volume of blood in the patient remains the same. The trial began in 2018 and will continue over the next 2-3 years, or when the first 1,000 patients are completed, whichever comes first.
To date there have been no published results but the anecdotal reports have been promising. Several patients have reported improved memory, stamina, sex drive and improved feelings of well being.
If infusing the plasma from younger people sounds a little too gruesome for you, don’t be discouraged. Scientists are working to identify the factors within young blood which might be responsible for the positive effects. This would allow the individual factors to be isolated and delivered in a targeted medicine.
Blood consists of over 10,000 factors so it is a difficult task identifying the exact constituents responsible for the beneficial effects seen in the older mice, however a number of studies have already identified several constituents which seem promising. The most promising discoveries to date include GDF-11, TIMP-2, Oxytocin, and MANF, each of these is discussed in more detail below.
GDF-11 (Growth Differentiation Factor 11)
GDF-11 is a protein found in the blood of all mammals. A team at Harvard has claimed that the levels of GDF-11 in the blood of mice declines as the mice age, and therefore is more prevalent in younger mice. The team injected GDF-11 into older mice and was able to show that the muscle density in the older mice improved to youthful levels (1). The findings earned the team the award for scientific achievement of the year in 2014.
Several members from the Harvard team have since founded a company, Elevian which is investigating human applications of GDF-11 and other factors. They believe these factors may be able to restore the body’s natural regenerative capacity, to address a root cause of age-associated disease.
So far there have been no results from clinical trials where humans have been administered with GDF-11 however Biohacker Steve Perry has been self-experimenting with GDF-11 since 2014. Since 2014 Steve has enlisted over 100 volunteers in his study. This is not a double-blind placebo-controlled study so the results should be read with caution, but it is worth a look.
Steve Perry claims that many of the volunteers in his study reported improvements in blood pressure, heart rate variability, resting pulse rate, blood glucose, hand grip strength, reaction time, memory, eye sight, smell, hearing, and for some their grey hairs disappeared! (2)
GDF-11 is not FDA approved and the risks associated with supplementing GDF-11 in humans are not yet known, therefore we would caution against experimenting on yourself. In one study GDF-11 was shown to be damaging to the liver (3). To minimize risk the doses used by the participants in Steve’s study were extremely low (requiring dilution by a factor or hundreds of thousands) and the participants in Steve’s study closely monitored their vitals, and other biomarkers on a daily basis.
GDF-11 is available for purchase on the internet however rather than supplementing GDF-11 directly, you can boost it more naturally using regular exercise. People who exercise regularly over the long term demonstrate higher levels of GDF-11 then people who lead sedentary lifestyles (4).
TIMP-2 (Tissue inhibitor of metalloproteinases 2)
TIMP-2 is a human gene and protein. One study showed that injecting mice with blood plasma from a human umbilical cord, resulted in significantly improved cognitive function. Elderly mice that received the plasma were quicker to learn and remember the escape hatch location in a maze, they were better at learning associations between a room and an electric shock and faster making nests for their babies.
The team who conducted this experiment proposed this was due to TIMP-2. TIMP-2 levels start high when we are born and decline throughout life, similar to GDF-11.
When TIMP-2 was injected directly into the older mice they observed cognitive improvements similar to those mice that were injected with the umbilical cord plasma. Also when TIMP-2 was removed from the umbilical cord blood plasma before it was injected, no cognitive function improvement was observed (5).
The mechanism by which TIMP-2 works is not yet understood. A clinical trial to see if young human blood plasma can slow the cognitive decline of people with Alzheimer’s is being conducted. So far there are no studies assessing the safety of TIMP-2 supplementation in humans.
Sugars from the Aloe Vera plant have been shown to induce TIMP-2 production in the skin of rats when applied directly to wounds (6). Potentially Aloe Vera products may be able to increase TIMP-2 levels in humans, although this has not yet been demonstrated.
Oxytocin
Oxytocin is a hormone produced in the body which plays a role in social bonding, sex and childbirth. It is often referred to as the ‘love hormone’. Oxytocin is released when we hug someone or hold their hand, it promotes feelings of trust, romance and friendship, it also increases libido. Oxytocin is released after birth to promote bonding with the baby.
Similarly to GDF-11 and TIMP-2, Oxytocin declines with age. One study demonstrated that Oxytocin has beneficial effects on maintaining healthy muscles and healing in old mice. Older mice who were injected with Oxytocin recovered faster from muscle injury than mice who were not treated with Oxytocin. The same study also demonstrated that when Oxytocin is blocked in young mice, their ability to repair muscles declined (7).
Unlike GDF-11 and TIMP-2, Oxytocin is already approved by the FDA for clinical use in humans. Pitocin is a synthetic form of Oxytocin used to help with childbirth. Also you can easily increase your own levels of Oxytocin naturally through a variety of activities including hugging, sex and, in women, nipple stimulation. Engaging socially, or playing with dogs has also been shown to increase levels of Oxytocin.
MANF (Mesencephalic Astrocyte-derived Neurotrophic Factor)
MANF is protein which is secreted by the body in response to stress. MANF is responsible for regulating metabolism and immune response. It also, like the other factors mentioned, declines with age.
In one study it was observed that MANF promoted the activation of immune cells which promoted neuroprotection and tissue repair (8). Researchers have also shown the same mechanism protects against liver damage in older mice and extends lifespan in flies.
Flies genetically engineered to express less MANF suffered from increased inflammation and shorter lifespans. Similarly older MANF deficient mice showed signs of bad health. When older mice shared a blood supply with MANF deficient younger mice, they did not see the benefits they would if sharing with younger normal mice (9).
There are several ways to increase your natural levels of MANF with the safest and easiest being fasting (10), and exposure to heat (e.g. via a sauna) (11).
Up next
In the second part of this series we will discuss some more practical approaches to anti-ageing, including fasting and various supplements which are readily available.
References
1. https://www.ncbi.nlm.nih.gov/pubmed/23663781
2. https://www.youtube.com/watch?v=Oe9mDFRJFuk
3. https://www.fasebj.org/doi/abs/10.1096/fj.201800195R
4. https://physoc.onlinelibrary.wiley.com/doi/full/10.14814/phy2.13343
5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5586222/
6. https://www.ncbi.nlm.nih.gov/pubmed/24491493
7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4512838/
8. https://www.ncbi.nlm.nih.gov/pubmed/27365452
9. https://www.nature.com/articles/s42255-018-0023-6