As almost anyone is aware, cardio-vascular diseases (or CVD as they are usually referred to) are one of the top causes of death in the developed world. While it is our opinion that dietary fat intake has been unfairly blamed as the main culprit, that is a topic for another time, or blog post. Now we would like to explore another much less known cause: autophagy, or rather lack thereof, as it affects our hearts.
Heart problems can be divided in 3 broad categories: the heart muscle itself, cardiac vasculature (i.e. veins and arteries around the heart) and impaired conduction of electrical impulses. The two main consequences are (1) your heart having a harder time pumping blood around and (2) abnormal blood pressure.
The most important factor is the cardiac muscle cell, or cardiomyocyte. As we grow older, the rate at which cardiomyocytes degrade increases, and the rates at which they get replaced decreases. The replacement rate of cardiomyocytes decreases from 1% in early age to 0.45% in advanced age (see here). This is compounded by the fact that cardiomyocytes become more sensitive to reactive oxygen species, or ROS, as we age. Production of ROS in our metabolism is inevitable as they are a product of normal metabolic processes. As cardiomyocytes are lost and not replaced, fibroblasts fill the vacant space with collagen, progressively stiffening the heart muscle (fibroblasts are cells that produce collagen and other connective tissues).
As a normal part of the aging process, our arteries become progressively thicker and stiffer, causing elevated blood pressure.
The end result of these changes is that heart function is impaired in both the ability to push blood out and suck blood in. In order to compensate, the heart muscle grows. Since we number of cardiomyocytes is decreasing over time, muscle growth is obtained by increasing the size of the individual muscle fibers. While this strategy works initially, over time the process degrades and leads to heart failure (see here).
ATP (adenosine triphosphate) is energy currency of most living creatures. ATP is produced by mitochondria, which are the energy factories of living organisms. All our cells contain mitochondria (some more, some less). Because the heart is an extremely hard-working organ, it needs to produce large amounts of energy, and as a result cardiomyocytes are composed of 40% mitochondria, which is a much higher ratio that most other cells in the body (see here).
As our cells age, they accumulate damage, and produce additional ROS. But ROS, which is also a normal byproduct of mitochondrial energy generation, also produces damage in our cells, and this creates a negative feedback loop, where ageing cells keep producing more and more ROS.
Autophagy is a process by which damaged proteins and organelles (specialized structures within a cell, like mitochondria) are removed from the cell. This serves the dual purpose of removing potentially toxic molecules and to recycle the building blocks of these damaged parts during times when cells are nutrient-deprived.
Autophagy consists of 3 steps (extremely simplified version):
1. Initiation: something called a phagophore is formed. It will become part of the structure that collects the damaged molecules
2. Elongation: various proteins and genes are engaged in the transformation of the phagophore into the autophagosome, which then collects damaged molecules for degradation. The autophagosome’s job is to scoop up defective proteins and organelles
3. Maturation/fusion: the autophagosome fuses with a lysosome (which contains acidic substances, sort of like a self-contained, travelling stomach), forming an autophagolysosome. The whole thing will then be broken down into constituent parts
There is also a specialized form of autophagy called mitophagy, where a similar process degrades damaged mitochondria.
Our bodies alternate between a state of building up (anabolism) and tearing down (catabolism). Autophagy is triggered when our bodies sense that nutrients are getting depleted (i.e. we haven’t eaten in a while), and we need to recycle defective parts so that they can be used to rebuild other important structure, or as energy sources.
There is strong evidence that both autophagy and mitophagy decrease with age in various types of tissue, including the heart (see here). It is unclear why that happens, though a plausible theory is that over time our cellullar systems are overburdened by the increased ROS generation and associated oxidative stress.
Several studies (such as this) support a theory that defective mitochondria, which tend to increase in size over time, become too big to be contained by autophagosomes. As a results, these damaged mitochondria are not cleared out of the cell, while normal sized mitochondria are cleared by mitophagy normally. The end result is that over time the proportion of giant, dysfunctional mitochondria increases over time, together with decreased respiratory function and ATP production, and increased ROS production.
Autophagy and Sirtuin 1
Sirtuin 1 deacetylates several autophagy-related proteins, which increases autophagy. It also deacetylates FoxO1 in the heart during fasting, which causes upregulation of autophagy mediators. Caloric restriction (CR) and resveratrol activate Sirt1. We know that Sirt1 is responsible for many of the benefits of caloric restriction and resveratrol because mice deficient in Sirt1 do not show enhanced life span in response to the treatment. We also know that in yeast and in C. Elegans, knocking down autophagy genes abolishes the longevity enhancement benefits of caloric restriction and resveratrol. This points to the fact that Sirt1 is required to get the longevity benefits of CR and that autophagy plays a role in it.
Autophagy and AMPK
AMP-activated protein kinase, more commonly referred to as AMPK, is another nutrient sensing molecule in the cell, just like mTOR. Its main functions are:
- regulating metabolic homeostasis, i.e. maintaining the energy balance of our metabolism and;
- mitochondrial biogenesis: the creation of new mitochondria
It also regulates autophagy, through the following mechanisms:
- it inhibits mTOR
- it activates ULK1, which is an enzyme that activates the early steps of autophagy when autophagosomes are created, in response to amino acid withdrawal
- it raises NAD+ levels in the cell, which activates Sirt1 mentioned above
AMPK is activated by several molecules, metformin being one of the better known ones. The latter is one of the main drugs given to diabetic patients to control their blood/sugar. Exercise and CR also activate AMPK.
Autophagy and mTOR
One of the most important enzymes related to nutrient homeostasis is mTOR. It integrates inputs from Sirt1, AMPK and other pathways and acts as the central nutrient sensing signaling hub. mTOR inhibits autophagy by throttling ULK1. While it has many cellular functions, its regulation of autophagy is believed to be the main mechanism through which mTOR inhibition grants life-extending benefits. mTOR stands for mammalian target of Rapamycin, which is an antibiotic that down-regulates mTOR. It gets its name from Rapa Nui, which is the local name for Easter Island, where it was discovered. As you might have guessed, CR is another way to attenuate mTOR.
There is a class of molecules called caloric restriction mimetics, which can chemically reproduce certain effects of CR. Spermidine, hydroxycytrate, resveratrol, pterostilbene and curcumin, along with several other well-known supplements, all belong to that group. They work by deacetylating authophagy-related proteins using various pathways. It is likely that combining exercise and caloric restriction together with caloric restriction mimetics will give an additional boost to your autophagy.
If, like us, you believe that autophagy is important to maintaining your health (not just heart health), see the link below to purchase Autophagy Stack, the first and only supplement formulated to boost autophagy.