It’s been bugging me for more than a year now. What can we do right now to slow aging?
This is one of the reasons I wrote Periodic Fasting, telling stories about people who used calorie restriction in the Middle Ages to live past 100.
It’s also one of the reasons for which I don’t obsess about protein intake, especially in light of the recent research showing increased healthy lifespan when protein is restricted. But what other non-expensive strategies can we implement to make it work until we have the technologies available for prolonging life indefinitely? As far fetched as it may sound, this may be possible in the not so distant future.
There are a few researchers whose work I follow closely. Last week I received an alert that one of them has released a new paper (as of April 2015) in collaboration with 25+ other researchers. Let me try and translate it into simple language so that everyone may understand what it implies.
Current Interventions to Slow Aging
This article is free (currently), so if you want to take a closer look and don’t want to take my words for granted (which I would encourage you not to) here it is.
30 researchers have put their name on this paper and the 4 I’m mostly familiar with are: David Sinclair, Luigi Fontana, Valter Longo, and Nir Barzilai. The 4 major approaches proposed by them refer to :
i) dietary interventions mimicking chronic dietary restriction
This can be seen as periodic fasting (or periodic fasting mimicking diets), protein restriction, etc .
ii) drugs inhibiting the growth hormone/IGF-1 axis
iii) drugs inhibiting mTOR-S6K pathway
iv) drugs activating AMPk or specific sirtuins.
I’m not sure why they focus on drugs to reduce or increase the activity of these pathways, when most of the outcomes could be achieved by fasting and/or caloric restriction. Of course, fasting and CR are uncool because they make you hungry (ironic). At least that’s what’s been promoted out.
As I wrote in my book, I am able to eliminate hunger and I’ve been doing daily intermittent fasting for almost a year and a half (at this point – May 2015) with 18-20 hours of fasting and 6 hours of feeding windows. There are times when I deviate from the rule, such as days when I have 4-6 meals and I over-consume calories. Then there are times when I fast for more than 40 hours. My current approach focuses on a low-calorie-very-low-carb-ketogenic diet, rich in plants foods, healthy fats, and low in meat. The idea is to consume a nutrient rich ketogenic diet that, over the long term, is very likely to eliminate food cravings and hunger. This allow for calorie restriction without feeling hungry. Timing (eating for circadian synchronicity) plays an important role as well. This strategy (along with other interventions) works wonders for me and I’m not sure how it may work for others.
Getting back to the research study :
DR (dietary restriction) protects against diabetes, cancer, cardiovascular disease, sarcopenia, and neurodegeneration of certain brain regions in rhesus monkeys and also extends lifespan (Mattison et al., 2012; Colman et al., 2014). In humans, long-term DR causes several metabolic and molecular changes that protect against age-related pathologies, including changes in markers for type 2 diabetes, hypertension, cardiovascular disease, cancer, and dementia (Cava & Fontana, 2013).
Tell that to someone who obsesses about food every 3-4 hours.
Intermittent fasting (IF) and prolonged fasting (PF), as mentioned by researchers, were seen to downregulate Tor-S6K and Ras-adenylate cyclase-PKA, which are glucose sensing pathways in yeast. Similarly observed in worms and mice, these changes increase resistance to toxins and extend longevity.
Although the effect of chronic cycles of PF on healthspan is not known, these studies point to PF, which could be carried out in humans as infrequently as once a month or less, as a potent inducer of protective systems and a potential alternative to chronic CR and IF.
A number of PF and IF clinical studies in humans are yielding very promising results in support of the possibility that they are sufficiently safe and effective to be considered for long-term clinical trials focused on healthspan (Longo & Mattson, 2014). 
Further, researchers support the benefits of combining vegetarian diets and periodic fasting. I would be careful when promoting drastic dietary approaches because they may fix things on one side, while disturbing processes and bodily functions on other sides. That’s why I don’t advocate for 80%+ fat diets or for full vegetarian/vegan diets, unless severe medical conditions would call for that.
PF and IF have few adverse effects, but could be dangerous for subjects of very low BMI, those who are frail and old, and patients with diabetes receiving insulin or insulin-like drugs. 
Protein Restriction or selective AA restriction
Restriction of calories in the form of protein contribute to the benefits of DR on animal longevity (Gallinetti et al., 2013; Mirzaeiet al., 2014). Restriction of individual essential amino acids,
including methionine and tryptophan, can also extend longevity (Spindler, 2009). 
This often leads to the down-regulation of mTOR and the activation of GCN2. While overall reduced protein intake seems to elicit positive effects on longevity, reducing particular amino acids is beneficial as well :
– methionine, serine, threonine, valine restriction in yeast
– methionine restriction in flies
In mice :
– protein/amino acid restriction also offers health benefits in models of acute stress and chronic disease.
To date, very few studies have been performed in humans on the potential beneficial effects of protein and/or amino acid restriction on aging processes or age-associated chronic diseases (Cavuoto & Fenech, 2012; Mirzaeiet al., 2014).
It’s not easy to quantify the changes that results from protein restriction in humans (yet), which is one of the possible limitations of the current study. Yet, we do know that increased IGF-1/insulin and mTOR signaling are, invariably, seen in tumor tissue.
Should we wait until research proves it unequivocally? I will personally not.
In the second part of the paper, the researchers focus on pharmacological interventions that would mimic caloric restriction. Say what?
Again, I would not use drugs that could possibly (most likely) lead to additional negative effects when I can fast and/or use caloric restriction for significantly better results. Researchers discuss about increasing the activity of AMPk (energy sensing pathway) and SIRT1 in a background of caloric restriction/fasting which is considered to increase autophagy, DNA repair, and overall improved cellular and sub-cellular health. I discussed these processes in detail in Periodic Fasting.
I’m not completely against using drugs. But why use them, when you can do it naturally with mostly no side effects!?
Compounds that activate SIRT1 and AMPk
The deacetylases known as sirtuins (SIRT1 to 7) promote longevity in diverse species and could mediate many of the beneficial effects of DR (Satoh et al., 2013) 
Some of the most potent compounds come from the plant world: flavones, stilbenes, chalcones, and anthocyanidins. As mentioned by researchers, resveratrol (found in red wine) is still considered the most potent.
AMP-activated protein kinase (AMPK) is a conserved, energy-sensing serine/threonine kinase that is activated when cellular energy levels are low, resulting in increasing levels of AMP (Ruderman & Prentki, 2004). 
Without mentioning all the drugs that have been developed to activate AMPk, I would say that long-term calorie restriction and/or practicing IF and PF may be the most effective approaches. Curiously enough, recent research showed that ketogenic diets increase AMPk activity even when calories are overconsumed (hypercaloric diets) . It is also interesting that metformin was shown to activate AMPk. However, as researchers point out, we have to be cautious :
…recent evidence indicates that metformin also promotes inhibition of mitochondrial glycerophosphate dehydrogenase and gluconeogenesis, suggesting that only a partial understanding of the mechanisms of action of this powerful drug is known, and that further
studies are necessary to determine whether it should be considered for treating generally healthy or relatively healthy populations (Madiraju et al., 2014).
I know that several healthy folks from the bio-hacking community use it for life-extension purposes, but I would be more prudent about that in light of these recent findings.
In the end of the paper, authors give a few suggestions/reminders on what we may implement for the purpose of increasing life and healthspan now. They mention using:
1. Intermittent or prolonged fasting
2. Mild CR in combination with a low glycemic index diet and protein restriction
3. Inhibition of GH/IGF-1 axis
4. Inhibition of TOR-S6K signaling
5. Activation of SIRT1 and AMPk
If the first two are followed appropriately, the last three may come as results. So you would not have to use drugs to inhibit/activate these pathways (3,4, and 5). Of course, nobody would gain financially if they tell you to restrict calories or not to consume food at all.
Supplement companies (especially protein supplements) would go bankrupt if the average Bro finds out that muscle loss is minimized with fasting and it could be reduced to 0 under certain circumstances.
Until further research gives us safer approaches and until some wild technology would allow us to download our conscience and transcend, simply (and cheaply) restricting food/practicing IF/PF may make you healthier and help you live longer.
For keeping things simple, find the rest of the resources in the references section of the first paper.
1. Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., … & Fontana, L. (2015). Interventions to Slow Aging in Humans: Are We Ready?. Aging Cell.
2. Draznin, B., Wang, C., Adochio, R., Leitner, J. W., & Cornier, M. A. (2012). Effect of dietary macronutrient composition on AMPK and SIRT1 expression and activity in human skeletal muscle. Hormone and metabolic research= Hormon-und Stoffwechselforschung= Hormones et metabolisme, 44(9), 650-655.