Calorie restriction remains the surest path to increased longevity and resilience to diseases of aging across many organisms including humans. As an added bonus, it is a good to lose those extra pounds especially during the holidays. Calorie restriction seems to affect many aging pathways. If we affect these pathways in a positive manner we can slow down and perhaps turn back the clock of aging.
Many of the beneficial effects of calorie restriction appear to be due to modification of specific nutrient-responsive pathways such as the insulin/insulin-like growth factor (IGF-1 which can be considered the active form of human growth hormone) pathway, the target of rapamycin (TOR) signaling pathway, and the NAD+-dependent sirtuin genes. These are the same pathways that control stem cell aging. Remember, how our stem cells age is how we age. For example, genetic modulation of any one step in the IGF-1 signaling pathway enhances lifespan in many species. Rapamycin, the first small molecule found to extend lifespan in mammals, works by inhibiting the nutrient-responsive TOR pathway. Finally, the mitochondrial NAD+ pathway stimulates the sirtuin 3 (SIRT3) gene which is required for increased production of ATP and mitochondrial health.
These pathways operate together as a very complicated system. The extent to which that system operates in harmony, or otherwise, has a profound effect on our health and aging. In fact, it could be said that they control our fate.
Calorie restriction on the surface is great but it is not practical. However, one dietary regimen that mimics the healthspan-promoting effects of caloric restriction is the Ketogenic Diet (KD), which consists of high-fat and low- or no-carbohydrates. When glucose is not readily available, fat is broken down by the liver into glycerol and fatty acid molecules. The fatty acid is then broken down further, in a process called ketogenesis. During this process, acetoacetate is the first ketone body that is produced. Acetoacetate is then converted into either Beta-hydroxybutyrate (BHB) or acetone. Acetone is the least abundant ketone body, but it may be produced in higher quantities when you first start the ketogenic diet. This is a reason while some people when first starting the ketogenic diet have bad breath for a short time. As your cells adapt to carbohydrate restriction, BHB becomes the most prevalent ketone body and your brain and muscle cells start using it as their primary fuel. In fact, when you are keto-adapted, ketones can supply up to 50% of your basal energy requirements and 70% of your brain’s energy needs.
Let us do a quick comparison between a ketogenic diet and a regular diet which depends on glucose. Glucose is the primary energy source for almost every cell in the body. This is because it can be broken down into energy much more quickly than any other fuel source, and it does this without the help of the mitochondria (the main energy producing component of the cell). Using glucose for fuel, however, comes with some negative effects. What we gain in quickness, we lose in efficiency.
During the process of sugar burning, more free radicals (harmful compounds that can cause cell damage, also called Reactive Oxygen Species [“ROS”]) are released and less energy is created than when we use ketones and fat for fuel. The ROS harm cells in many different ways and advance aging on many different levels. On the other hand, Ketones are a more efficient fuel source that inhibits the production of free radicals and reactive oxygen species. This leads to a host of benefits, especially for the brain cells that use ketones instead of sugar for fuel when glucose levels are low. For example, studies done on people with different types of cognitive issues from Parkinson’s disease to epilepsy confirm that using ketones as fuel can improve brain function tremendously. However, the benefits of burning ketones for energy doesn’t stop in the brain. Many other cells like muscle cells also benefit from the use of ketones (more on that later), but you can’t reap these benefits unless you use up your sugar reserves first.
A standard Ketogenic Diet efficiently reduces body weight to its normative level and stimulates liver synthesis of ketone bodies. Ketone bodies are released into the bloodstream and provide energy-efficient fuel to highly oxidative organs, including liver, brain and the heart. In many respects the Ketogenic Diet is similar to calorie restriction in that both produce similar beneficial side effects.
There is certainly nothing new about the Keto-Diet. It has been mentioned by many, yet few have a good understanding of what is really going on. We became more aware of it as we developed our Advanced Cellular Repair Division. By understanding the essential mechanics of the Keto-Diet, we can better understand why it is successful in so many aspects of health including stem cells. I conducted a survey of articles written on the Ketogenic diet and found that most of them are parroting the same information that misses the most salient points. For example, they are not aware of the effect that ketone bodies have on aging pathways which have a profound effect on our health landscape.
The ketogenic diet tries to bring carbohydrates down to less than 5% of a person’s daily caloric intake – which means eliminating most grains, fruit, starchy vegetables, legumes and sweets. Instead, it replaces those calories with fat. Typically, proteins are not a problem although there exists a misconception amongst many low-carb, high-fat advocates that excess protein can turn into sugar in your bloodstream through a process called gluconeogenesis and knock down your ketone levels.
In practice, there is no evidence that consuming excess protein will increase glucose production from gluconeogenesis. Gluconeogenesis (GNG) is a metabolic pathway that allows your liver and kidneys to make glucose from non-carbohydrate sources. To clarify, you don’t need to eat any high-carb foods to survive, but make no mistake, your body needs glucose and glycogen to keep you healthy (even on ketosis) and it will get this via survival mechanisms like gluconeogenesis. There are a handful of cells in your body that can only use glucose to survive, including red blood cells, kidney medulla (inner part of the kidney), testicles and some parts of your brain. Ketones can cover up to 70% of your brain’s energy needs while glucose from GNG covers the rest. The other organs can’t metabolize ketones at all, so gluconeogenesis provides them with enough glucose to remain healthy.
One of the mainstays of the Keto diet is fat. That fat is turned into ketone bodies, which are an alternative energy source to glucose derived from carbohydrates. Ketones from fat are the only fuel the brain can use in the absence of glucose. Most people are well aware that sugars are inflammatory. When we block glucose metabolism we are having a suppressive effect on inflammatory genes. When you start affecting genes you start affecting cellular pathways.
The following diagram is of the upmost importance in illustrating the message we are trying to convey. In this diagram, instead of “Stem Cell Aging Pathways” we can easily substitute the name “Human Aging Pathways” for how our stem cells age are how we, in turn, age.
The Ketogenic Diet seems to have a direct effect on many of these aging pathways so let us examine more closely how this happens. No generally accepted theory has been proposed to explain the observation that caloric restriction extends lifespan. However, we now realize that the life extension produced by caloric restriction can be replicated by the metabolic changes induced by ketosis. Ketone bodies protect neurons against multiple types of neuronal injury and the underlying mechanisms are similar to those of both calorie restriction and the ketogenic diet. The following diagram gives an idea of some of the actions of ketone bodies.
The diet’s high-fat, low-carbohydrate composition reduces glucose utilization and promotes the production of ketone bodies. Ketone bodies are a more efficient energy source than glucose. They improve mitochondrial function and biogenesis, with increased health-span, lifespan and cellular energy production. When we are improving mitochondrial function, we are stimulating the Sirtuin genes which can be found on the first diagram as Sirt1,3, and 6. These same Sirtuin genes are the same ones that are stimulated by vigorous exercise, certain supplements such as Resveratrol, Pterostilbene, NAD, and finally calorie restriction.
Thus, we can see the ketone bodies can dramatically affect the Sirtuin genes to help up-regulate the production of ATP by stimulating the mitochondria. In many anti-aging circles, ATP stimulation is considered one of the holy grails. Ketone bodies as a fuel source are more efficient to burn into energy. Ketone bodies require only one molecule of NAD+ per molecule of Co-enzyme A, whereas glucose needs 4 molecules of NAD+. As we can see, ketone bodies as fuel allow us to have more NAD available. Co-enzyme A is important component in the Krebs cycle. The Krebs cycle is where ATP is made. The more NAD+ available the more ATP that can be produced.
Also important is the fact that ketone bodies go beyond being used as a fuel source. They themselves perform signaling activities in a way similar to growth factors. Intriguingly, the ketone body (which is also called BHB) might also be a metabolic intermediary, facilitating the benefits of calorie restriction and fasting. Long viewed as a simple carrier of energy from the liver to peripheral tissues during prolonged fasting or exercise, βOHB or Ketone bodies also possess signaling activities. It therefore joins a small but growing list of metabolic intermediaries that affect gene expression via modifications of the DNA. These changes on the DNA ultimately affect the production of messenger RNA. Messenger RNA then turns on certain genes by giving them commands to produce certain growth factors etc. The following diagram gives us an idea of some of the wide-ranging effects of ketone bodies in our bodies, many of which are the result of Ketone body signaling.
These ketone bodies and their intermediaries may be key links between variations in the cellular environment and the epigenetic changes associated with increased health-span and lifespan. In simple terms, Epigenetics is the study of biological mechanisms that will switch genes on and off. Epigenetics affects how genes are read by cells and subsequently whether the cells should produce certain proteins.
Environmental factors such as nutrition dramatically alter cellular metabolism and many also alter the epigenetic regulation of gene expression. Ketones will increase the metabolic coenzyme nicotinamide adenine dinucleotide (NAD), a marker for mitochondrial and cellular health. Furthermore, NAD activates downstream signaling pathways (such as the sirtuin enzymes) associated with major benefits such as longevity and reduced inflammation. Thus, increasing NAD is a coveted therapeutic endpoint.
The literature is now ablaze with information on NAD and, early in 2018, Time Magazine presented an article calling NAD based supplements a possible true “Anti-aging Pill”. Based on differential NAD+ utilization during glucose vs. ketone body during energy generation, it appears that a Ketogenic Diet will increase the NAD+/NADH ratio. The more NAD+ available the more ATP that can be produced. ATP production is thought to be a key factor in health and anti-aging.
What else do ketone bodies stimulate? Another important pathway in the body is called the NRF2 pathway. The NRF2 (nuclear factor erythroid-derived 2-related factor 2) pathway is the cellular antioxidant system. The Nrf2 pathway has been referred to as the master regulator of antioxidant, detoxification and cell defense gene expression. We can think of Nrf2 pathway as a “level switch” within our cells that senses the level of oxidative stress and other stressors and turns on internal protective mechanisms. Nrf2 is a potent modulator of antioxidant response and can rapidly target oxidative stressors. Ketone bodies increase mitochondrial glutathione levels by activating the Nrf2 pathway, thus reducing oxidative stress. It modulates the ratio between the oxidized and reduced forms of nicotinamide adenine dinucleotide (NAD+/NADH) which ultimately raises the ATP production. The following diagram shows the NrF2 pathway. We can see the difference between a normal cell and a cell that has suffered from oxidative stress.
Ketone bodies are also a stimulator of Autophagy. Autophagy is a necessary part of our survival because it involves killing off pathogens and cells that are potentially dangerous. It involves recycling old, damaged cellular parts into newer ones to keep our bodies free from disease. Below is a diagram that shows the principle of Autophagy.
One characteristic of aging is the accumulation of damage, and this is largely due to the failure of autophagy to attain normal functional levels. It can be seen that bringing levels of autophagy to youthful levels can ameliorate aging by clearing out damaged parts of the cell. Cells use autophagy to get rid of damaged proteins and organelles, to counteract the negative effects of ageing on the body. Most anti-aging treatments and protocols have something in common: they all cause an increase in autophagy. Autophagy is central to extending lifespan and to avoiding the diseases of aging.
Ketone bodies also seem to have a significant impact in the field of Cellular Senescence. Although senescent cells can no longer replicate, they remain metabolically active and commonly adopt characteristics consisting of pro-inflammatory growth factors. These cells are capable of doing damage not just on a molecular level but to the entire body. There is much interest on many different fronts in the field of cellular senescence. Lately, senescent cells have frequently made the headlines as they are a very promising target for medical intervention to delay or even reverse some aspects of aging.
While a certain number of senescent cells is tolerable and even beneficial, the accumulation of senescent cells in old age drives several age-related pathologies. We are well aware that senescent cells can have a significant impact on the success of stem cell treatments. My feeling is that the control and elimination of senescent cells may be the next big breakthrough in anti-aging science and other medical fields. The following diagram shows how senescent cells can cause damage on many different levels.
Senescent cells will accumulate growth factors, proteases, and inflammatory factors that disrupt normal tissue function. Senescent cells have long been implicated in aging and decreased success in stem cell procedures. By contrast, cellular quiescence is a reversible state of arrested growth. Quiescent cells do not divide but, under the right conditions, they can re-enter the cell cycle and divide again. This state usually occurs when nutrition or growth factors are lacking, and it is thought to be a way that cells can avoid entering a senescent state. The cellular quiescence mechanism also helps cells to preserve stemness and resist stress to their genes. Senescent cells can no longer divide and multiply. Researchers have found that ketone bodies can promote cell division and prevent cells from becoming senescent.
Although the above diagram is somewhat technical, it shows the difference between a quiescent cell and a senescent cell. We see that the senescent cell has a good deal of damage which has passed the point of no return. We now understand that a ketone body which is produced during calorie restriction or thru the Ketogenic diet will have anti-aging properties. In addition, the researchers found that, when the ketone body ( BBH also called β-Hydroxybutyrate) binds to a certain RNA-binding protein, this increases activity of a stem cell factor called Octamer-binding transcriptional factor (Oct4) in vascular smooth muscle and endothelial cells (Endothelium refers to cells that line the interior surface of blood vessels and lymphatic vessels, forming an interface between circulating blood or lymph in the lumen and the rest of the vessel wall). Oct4 increases a key factor against DNA damage-induced senescence.
It is thought that vascular aging is one of the root causes of whole-body aging. Another interesting fact is that there seems to be a distinct relationship between ketone bodies and a certain protein that stimulates what is called the P-53 gene. The P-53 gene is also called the tumor suppressor gene. It attacks senescent cells and causes their demise. At the same time, it can cause repair of some damaged cells making them younger.
As we can see, a ketogenic diet can be a very potent force for anti-aging and general health, having a profound effect on a number of aging pathways in a very beneficial manner. Ultimately, success in any stem cell procedure is dependent on successful manipulation of the stem cell aging pathways.
The above diagram demonstrates the principal hallmarks of aging, whose effects can be ameliorated by the Ketogenic diet. Clearly, the effects are far-reaching but, at the same time, we need to use common sense with this diet and remain free to “cheat” once in a while. An occasional slice of pizza is not that bad!
Thanks, Dr. Purita
February 15, 2019