Live fast, die… old? Intermittent fasting increases healthspan — and it may soon be a thing of the past
At some point in your life, you’ve probably been told that breakfast is the most important meal of the day — and maybe you believed it. Maybe it made logical sense that skipping what fuels your morning and gets you off to a good start would negatively impact your health. And maybe you inexplicably associate that phrase with an athletic, supportive (if overeager) tiger.
If that phrase triggers cravings for Frosted Flakes, Special K, or other morning staples, it's not a coincidence. The phrase was coined by Dr. John Harvey Kellogg himself — and it’s not totally off-base. But science indicates that skipping breakfast altogether could have some major health benefits.
Intermittent Fasting: What we Know
Intermittent fasting, which is periodically restricting caloric intake, was popularized in 2012 by the documentary Eat, Fast and Live Longer, has actually been around since Ancient Greece, when it was recommended by thinkers including Hippocrates, Plutarch, Plato, and Aristotle. And even before then, Cro-Magnons would go lengths of time without eating as a matter of necessity and survival, so you could say that intermittent fasting is the original Paleo diet. Besides the obvious correlation between eating less and losing weight, intermittent fasting has a number of health benefits stemming from what’s called autophagy.
Autophagy is a process cells use to maintain energy homeostasis and prevent the buildup of toxic materials. There are three main types: macro, micro, and chaperone-mediated. Macroautophagy is the best understood and most relevant to human longevity applications, so for the sake of brevity we’ll just refer to it as “autophagy” here.
Autophagy is triggered under a few different circumstances, most commonly when your cells don’t have enough nutrients. In simplest terms, it is when cells digest their own organelles. In slightly less simple terms, it’s when your lysosomes — organelles with digestive enzymes — break down old or damaged cell parts. When autophagy is triggered, double-membraned structures called autophagosomes enclose the to-be-digested material and then fuse with lysosomes. This gives the cell a source of energy, and prevents the cell from breaking down due to malfunctioning organelles.
That’s the idea behind intermittent fasting: wait long enough for autophagy to kick in, usually between dinner and the first meal of the next day. And it’s remarkably effective. Studies have linked intermittent fasting to DNA repair, increased antioxidant production, decreased inflammation, increased insulin sensitivity, reduced tumor growth, increased stem cell counts, and increased lifespan.
Autophagy has been linked to seemingly unrelated sources of life extension in other species as well: for example, microscopic C. elegans worms with a mutation in a gene called daf-2 that renders a receptor of an insulin-like growth factor ineffective typically have a marked lifespan increase; but when autophagy is inhibited, they do not live longer than other worms. Autophagy is at the center of what we know about increased lifespan, and you can trigger it for free.
So what’s the catch?
Intermittent fasting isn’t right for everyone; those who don’t want to lose weight or can’t do so safely, struggle with body image issues, or have to eat at regular intervals because of another health issue such as diabetes currently cannot receive the benefits of intermittent fasting or caloric restriction for longevity. Besides, it’s not that easy: it requires a lifestyle shift, decreased food intake, and passing up on midnight snacks at the very least.
But these drawbacks may soon be irrelevant. The longevity magic bullet of the future is not intermittent fasting: it’s caloric restriction mimetics.
Caloric Restriction Mimetics
CRMs are drugs and dietary supplements that have the same effect on your cells as triggering autophagy, and they’re not as far off as you may think. Let’s take a look at some of the most promising research that may be moving us towards the development of a pill that does the hard work for you.
Approach 1: G9a
Formally known as euchromatic histone-lysine N-methyltransferase 2, G9a is a histone-modifying enzyme that plays a key role in repressing genes that may trigger autophagy. By altering the proteins in your chromatin, it suppresses promoters of the LC3B, WIPI1, and DOR genes epigenetically. These genes are critical to autophagy, and their suppression therefore prevents the process from taking place.
However, when your cells are deprived of nutrients (or when the naive T-cells involved in autophagy are stimulated directly), g9a is removed, and the histones become conducive to the expression of autophagy genes. This suggests that g9a would be a good target for our Autophagy Pill: either getting rid of it directly or counteracting it for a period of time would result in overexpression of the genes that create autophagy. Alternatively, the c-jun N-terminal kinase pathway could be utilized to activate naive T-cells and trigger autophagy from scratch, with g9a following suit.
Approach 2: Spermidine
Contrary to intuition, spermidine is not a contraceptive, but a natural polyamine (an organic compound with three or more amino groups). Its concentration in the body depletes with age, which may be one of the less-talked-about causes of aging. Although you’ve likely never heard of it, it plays a crucial role in maintaining your health, and has been shown to prevent cardiovascular and neurological disease in mice, as well and stimulating anticancer immunosurveillance. It protects your mitochondira, prevents your stem cells from becoming senescent, decreases inflammation, prevents protein deacetylation, and is totally ineffective if autophagy is prevented.
So is spermidine just inducing autophagy? It’s hard to say. It did in yeast, flies, worms, and human cells. It had a couple other interesting result when it was introduced into these species, including:
- Lifespan extension
- Oxidative stress inhibition
- Epigenetic deacetylation of histone H3 to inhibition of histone acetyltransferase (this suppressed oxidative stress and prevented cell death)
But again, the prevention of necrosis, increased lifespan, and other bonuses did not occur when enhanced autophagy was prevented. This crucial link between spermidine and autophagy may make spermidine a candidate for a CRM that does even more than intermittent fasting. Spermidine and other polyamines can already be consumed through foods such as wheat germ and soybeans, and high levels of dietary polyamine consumption are associated with reduced cardiovascular and cancer-related mortality, but seeing as depletion of polamines produced internally leads to hyperacetylation, oxidative stress, premature cell deathspan, and a decreased overall lifespan, there would definitely be benefit to a drug that causes cells to produce their own spermidine — plus, DIY’s just more fun.
Approach 3: Gene Therapy
Although it may be farther down the road, gene therapies inducing overexpression of certain genes related to autophagy could be promising for human life extension. Atg5, in particular, may be a desirable target, as it activates autophagy and extends lifespan in mice.
Another option is Atg8a. Overexpression of that gene in the neurons of fruit flies increased their lifespans, and reduced the buildup of toxins in their neurons. However, like Atg5, it’s part of a future where elective gene editing for non-essential health improvements is commonplace, and therefore is not as feasible short-term as some other routes.
Approach 4: Beclin 1
The last biological trigger of autophagy with drug-potential is beclin-1, a protein that plays an important role in both autophagy and cell death. A study comparing the serum beclin-1 levels of healthy centenarians (100–104 year-olds), non-diabetic young people who had had heart attacks (28–39 year-olds), and healthy young people (27–39 year-olds) found that the centenarians had significantly higher beclin-1 levels than the young people. Although this does not necessarily indicate that they lived that long because of their high levels of beclin-1, the fact that centenarians are 3.4 times more likely than the average person to be in the 75th percentile or above for beclin-1 concentration is a good indication that there is a correlation between beclin-1 and the benefits of autophagy for longevity.
Interestingly, disrupting the beclin-1/BCL2 autophagy regulatory complex increased lifespan in mice. This further suggests a causal relationship between beclin-1 and longevity.
It’s likely that the future of human longevity is intertwined heavily with autophagy — after all, it’s fundamental to how aging works. And there are a number of genes, proteins, and processes that could be potential targets of longevity treatments centered around autophagy. Until then, check out what you can be doing right now to increase your own healthspan.
- Intermittent fasting triggers autophagy
- Autophagy is when cells digest damaged components
- Autophagy has numerous health benefits
- It may be possible in the near future to trigger autophagy with drugs
That’s all for now! Thank you for reading, and feel free to email firstname.lastname@example.org with any questions/compliments/accusations.
See you next time!