July 30, 2019

You may have heard last week's extremely interesting podcast with Dr. Sandra Kaufmann (pictured above trad climbing Camelback Mountain in Phoenix, AZ), entitled: The 7 Different Reasons You Age (& Potent, Proven Molecules To Enhance Longevity & Slow Aging).

Following our podcast, Dr. Kaufmann was kind enough to send over an excerpt from her new book—her thoughts on what the three big pathways of aging are, and exactly what you can do about them.

If you dig this excerpt from her book, then you can grab it here: The Kaufmann Protocol: Why We Age And How To Stop It.

Enjoy, and leave your comments, questions, and feedback below!

Introduction To Aging & Why We Age

Over the last decade, a number of metabolic pathways have been identified, and consequently dissected, that seem to exert control over organismal aging.

We will examine several of these in this chapter, but first, the question is how scientists suspected they might be there in the first place. This is where that part of the story begins.

It has been recognized, at least in the scientific literature, for over a hundred years that caloric or diet restriction can influence both healthspan and lifespan. Skinny people (not starving, just thin) tend to be in better health, and live longer than their overweight counterparts. The realization that this was true for humans, as well as other organisms, initiated a recent frenzy in the anti-aging quest.

As a result, almost every organism that can live in a laboratory setting has been food deprived and their lives quantified. So far, caloric restriction (CR), as defined by a 20%~50% caloric decrease from a standard diet, has been shown to prolong the mean and the maximum lifespan in dogs, rodents, worms, flies, fish and even yeast.

Higher up the evolutionary chain, the results are not so clear cut. Calorically restricted monkeys in one study lived longer, but in another they did not. Clearly, higher organisms are going to have more complex metabolisms with yet undefined confounding factors. Both studies did, however, show that caloric restriction increased the monkeys' healthspan by reducing risk factors for diabetes, cardiovascular disease, brain atrophy and cancer. In fact, most animals on the diet demonstrated a delay in a wide array of age-related diseases including cardiovascular diseases and neurodegenerative declines.

Working up to people, the phenomena is harder to prove. There was an interesting study however, of Japanese folks in Okinawa in 1997. In comparison to the rest of Japan, apparently this subpopulation had an above-average amount of daily physical exercise, a below-average food intake, and lived longer as compared to other Japanese people. However, when some of these same families moved to Brazil, they adopted a less healthy lifestyle that affected both their exercise and food choices. Consequently, they gained weight and their life expectancy dropped 17%.

So, following this train of logic, if we wanted to live longer we should just eat as little as possible. Living on the edge of malnutrition, however, is not easy. Your social life would probably suffer as well would the rest of your body. Caloric restriction diets decrease fertility, libido, wound healing and the potential to fight off infections, while they increase the risk of osteoporosis. Perhaps starving is not the answer, but fear not, there is more to this puzzle.

As I stated before, not all studies support the association of CR to improved healthspan and lifespan, but most do in almost all species scrutinized.

• “Caloric restriction with adequate nutrition is the only non-genetic, and the most consistent non-pharmacological intervention that extends lifespan in model organisms from yeast to mammals, and protects against the deterioration of biological functions, delaying or reducing the risk of many age-related diseases.”
• “Caloric restriction is by far the most effective environmental manipulation that can extend maximum lifespan in many different species.”
• The concept that “CR retards the aging process, delays the age-associated decline in physiological fitness and extends the life span of organisms of diverse phylogenetic groups, is one of the leading paradigms in gerontology.”

Questions then arise as to why this might happen, and then of course, how does this happen? Even more importantly, how can this information be utilized to help us?

To address the question of why, scientists have turned to the field of evolution. The going theory is that this response is an adaptation to preserve life in times of stress or famine.

The quest to understand how caloric restriction works initiated a new chapter in the study of human physiology. As a general overview, it was discovered that CR effects innumerable processes throughout the body. These range from affecting concentrations of various hormones, to the activity levels of different cell types. Most importantly however, especially for this conversation, scientists have uncovered several metabolic pathways that get either turned on or off under conditions of caloric stress that influence our time clock.

As time passes, even as I’m writing this book, new metabolic pathways and connections are being discovered that may or may not be critical to aging. For our purposes, however, we are going to focus on what I am going to call the ‘big 3’. These pathways measure the environment in terms of stress level, nutrient availability, oxygen concentration, and then determine the best course of action for the organism as a whole.

1. The First Marker Of Aging: AMP Kinase

The first of these pathways is controlled by an enzyme called AMP Kinase. Short for Adenosine Monophosphate-activated Protein Kinase, it’s a central regulator of cellular and organismal metabolism that plays a critical role in maintaining energy homeostasis. It is otherwise known as the Metabolic Master Switch.

It has also been labeled a “fuel gauge” or the “guardian of the energy status.”

The enzyme is an intracellular sensor that acts exactly as it is named. It detects increased levels of AMP (and ADP), which means that the cell is in a state of low energy. Hence, this also means that the levels of ATP are low, as AMP gets converted to ATP when there is adequate energy. Once a low energy state is detected, the enzyme reacts by seeking out replacement energy.

Thus, AMP Kinase promotes catabolic mechanisms (processes to break things into smaller pieces) that generate ATP while simultaneously inhibiting anabolic systems (processes that build different things) that require ATP.

This process is key to survival when an organism requires adaptive changes in growth, differentiation and process management under conditions of low energy. Whereas most cells have varying quantities of their own AMP Kinase, levels are highest in the liver, brain and skeletal muscle.

“Efficient control of energy metabolic homeostasis, enhanced stress resistance, and qualified cellular housekeeping are the hallmarks of improved healthspan and extended lifespan. AMPK signaling is involved in the regulation of all these characteristics via an integrated signaling network.”

In a nutshell, the activation of AMP Kinase does the following:

• In order to INCREASE the ATP production, the kinase:
  • Increases cellular uptake of glucose
  • Increases glycolysis, i.e. increases the breakdown of sugar to produce more energy
  • Increases fatty acid oxidation, i.e. breaks down fats for more energy
  • Triggers the acute destruction of defective mitochondria while stimulating new mitochondria to be produced
  • This can be considered as a “cash for clunker” system whereby the cell recycles broken or used mitochondria to get more efficient, newer models. This is actually called autophagy and will be discussed at length in a different section

• In order to DECREASE ATP utilization, the kinase:
  • Decreases fatty acid synthesis (essentially manufacturing less fat)
  • Decreases steroid synthesis
  • Decreases glycogen storage
  • Decreases protein production
  • Decreases cellular growth

In essence, the perceived shortage of energy puts the cell in a state whereby it can rebalance its own checkbook. It brings in energy from pre-owned fats and stored sugars and ceases the creation and storage of more fats and sugars. The net effect here is the preferential loss of fat, and decreasing the storage of fat at the cost of growth and development.

“It is known that AMPK stimulates energy production from glucose and fatty acids during stress and inhibits energy consumption for protein, cholesterol and glycogen synthesis.”

This pathway can actually be quite useful when exercising. When the skeletal muscles are stressed during training or a workout, AMP Kinase comes to the rescue. It increases mitochondrial biogenesis (creates more mitochondria), increases energy available to the muscle cells, and stimulates an increase in the blood supply to the muscle. Without AMP Kinase, the body would not be able to adjust to changes in workload.

There are also other housekeeping activities that have recently been linked to AMP Kinase, such as:

• Influencing circadian clock regulation
• Reducing oxidative stress
• Reducing inflammatory markers

So how do these things actually happen?

AMP Kinase is a protein consisting of three basic sub-units. One functions as the ON button (the catalytic unit); the other two initiate the processes. The ON button directly binds to AMP or ADP and alters the conformation of the rest of the molecule so that it can become phosphorylated, i.e., combined with a phosphate.

Once turned on, the molecule acts upon a number of substrates around the cell and around the body to effect change.

Very little survives the process of aging unscathed, and the activity of AMP Kinase is no different. In fact, “emerging studies indicate that the responsiveness of AMPK signaling clearly declines with aging.”

So, unfortunately, as we age and the activity of AMP Kinase declines, this causes a growing number of problems around the body. For example:

• Decrease in autophagy (intracellular recycling of proteins and organelles)
• Increasing oxidative stress
• Increasing inflammation
• Increasing fat deposition (The annoying belly fat that accumulates with age)
• Hyperglycemia (high blood glucose levels)

What usually triggers AMP Kinase?

• Low energy
• Ischemia (Lack of blood flow and resultant lack of oxygen and nutrients to an area)
• Anoxia (Lack of oxygen)
• Stimulation from fat-based hormones: leptin and adiponectin
• Exercise

Therefore, we have a situation where a necessary enzyme declines with age, bringing unwanted secondary effects that make the aging process even worse. In addition to this, the triggering list (with the exception of exercise) sounds rather unappealing.

The good news, however, and there had to be good news after all of this, is that we can pharmacologically improve the situation. The most famous of these compounds is metformin (glucophage). A well known and very common diabetic medication, it is also a mild inhibitor of the electron transport chain in the mitochondria and it precipitates a drop in the intracellular levels of ATP. The resulting increase in AMP triggers AMP Kinase, thus essentially faking an energy decline.

There is an entire chapter on metformin, so you will just have to wait to hear the other phenomenal things it can do.

In addition to metformin, there are several more natural compounds that trick the body into thinking it’s starving. Referred to as caloric restriction mimetics, they also trigger the production of AMP Kinase. Clearly, it is easier to fool the body into doing the right thing than to actually starve oneself.

Caloric mimetics triggering AMP Kinase include:

• Resveratrol
• Pterostilbene
• EGCg
• Quercetin
• Curcumin

Not only will these be discussed in detail elsewhere, they also have innumerable other fabulous traits that you are going to come to learn and appreciate!

Note from Ben: You can read my own thoughts and comments on metformin here, and I'd also recommend looking into Kion Lean as another mimetic!

2. The Second Marker Of Aging: The Sirtuins

The sirtuins are another beloved family of genes and proteins that play a huge role in anti-aging, and thus constitutes the second pathway that we are going to consider. Otherwise known as the Silent Information Regulator gene, this family regulates the bodies metabolic and growth pathways. Discovered in 2000, it was noted that if yeast had an extra copy of the gene, SIRT1, they lived 30% longer than average. If they lost a copy (they would normally have 2), their lifespans would be shorter.

As a side note (because it can get confusing), the genes are named in capitals like SIRT while the proteins that they code for are not, Sirt1

Much like AMP Kinase, the sirtuin family (genes and associated proteins) senses the environment in terms of energy availability, timing of daylight, environmental stressors and alters the metabolism to promote survival. Realizing this sounds familiar, sirtuin activity can, directly and indirectly, activate AMP Kinase activity, so many of the downstream effects are the same.

“The close relationship between AMPK and SIRT1 is evidence that energy balance effectually controls cellular responses via an integrated signaling network.”

Mammals (including people) carry the genes for seven members of the sirtuin family, cleverly named SIRT 1-7. The proteins Sirt 1, 6, and 7 tend to be localized in the nucleus, while Sirt 3, 4 and 5 are in the mitochondria and Sirt2 is in the cytoplasm.

SIRT1, discovered first and thus getting the #1 designation, is also the most researched of the bunch. The gene is located on the long arm of chromosome #10 (10q21.3) and the proteins it produces are localized in the nucleus, and thus govern the DNA. Like all of the SIRTs, it regulates the transcription of particular proteins, silences unnecessary genome sequences, and has myriad effects on epigenetic regulation. More specifically, it plays a role in the control of circadian rhythms, mitochondrial DNA transcription, the inflammatory pathways, and controls muscle wasting.

To make this easier, the following is a list of the genes (along with their personal information and effects):

• SIRT1:
  • Located in the nucleus
  • Circadian rhythm regulation (which is more important than you think)
  • Mitochondrial DNA transcription
  • Oxidative stress
  • Inflammatory pathways (NF-κβ)
  • Sarcopenia (muscle wasting)
  • Mitigation of metabolic dysfunction
• SIRT2:
  • Located in the cytoplasm and nucleus
  • Mitosis entry (cellular reorganization during cell replication and division)
  • Regulates fat tissue
  • Known to affect histones @H4K16 (thus an epigenetic modifier)
• SIRT3:
  • Located in the mitochondria
  • Orchestrates mitochondrial function
  • Increases production of superoxide dismutase
  • Apoptosis (getting rid of useless dead cells)
  • Affects brown fat expression
  • Known to affect histones @H3K9
• SIRT4:
  • Located in the mitochondria
  • TCA or Krebs cycle (Controls cycle which is a preliminary step in energy production)
• SIRT5:
  • Located in the mitochondria
  • Uric Acid cycle (Don’t worry about this)
• SIRT6:
  • Located in the nucleus
  • Controls inflammation through effects on NF-κβ
  • Telomeric preservation
  • Prevents diet-induced obesity
  • DNA repair
  • Extends lifespan
  • Known to effect histones @ H3K9, H3K56
• SIRT7:
  • Located in the nucleus
  • Controls nucleolar maintenance during cellular stress

As is readily apparent, this family of genes and consequent proteins are a well-connected and multifaceted family which you should get to know and respect. In the literature, the “sirtuins are now predominantly associated with government over longevity, disease prevention, and healthy metabolic function.”

The structure of the sirtuin proteins, while of course varying from one to the other, have three important conserved sites – the activation site, the NAD binding site, and the zinc-binding site.

There are two take-home messages here.

• First, there IS a NAD binding site, which means that the entire sirtuin family is useless without NAD. Thus, it is a necessary co-factor for the working function of the sirtuins. As we discussed in the mitochondrial section, NAD was a rate-limiting molecule that declines with age, seriously affecting cellular energy production. The same deficit in NAD can devastate all of the vital standard cellular functions controlled by the sirtuins and especially their anti-aging properties.

• The second take-home message is the zinc-binding site. If you recall, the superoxide dismutase or SOD enzymes 1 and 3 also are zinc-dependent. Therefore, it turns out that many micronutrients, like zinc, become especially important in order to maintain the innate anti-aging systems. Thus, micronutrient deficiencies can be catastrophic.

One of the most interesting, yet I believe under-appreciated, mechanisms is that of our circadian cycle.

We take it for granted that we snooze incredibly well when we are young, and then struggle to sleep as we get older. It is yet another one of those things people consider inevitable. But, as it turns out, the circadian cycle is controlled by a combination of SIRT1 and NAD. Interestingly, both of these control and are controlled by aging; both decrease over time and luckily, both deficiencies are easily remedied.

The circadian mechanism itself is controlled by the production of four different protein complexes, two of which are active during the day, the other two at night.

The first daytime complex is the CLOCK, aka the Circadian Locomotor Output Cycles Kaput. Located mainly in the suprachiasmatic nucleus of the hypothalamus (a small area in the brain), this family of proteins is actually a complicated network of several proteins.

The second daytime functioning protein family is called BMAL1 or Brain and muscle-ARNT-like 1.

Regardless, the two complexes work together and drive most of the oscillations in protein production in the body. Overall, they control up to 10% of the total transcribed genes.

The night time protein families are PERs (Period 1) and CRYs (Cryptochrome 1 and 2). These two work in conjunction to repress the activity of the first two. In essence, the circadian cycle is a constant battle with two against two. Interestingly, this process of inhibition by PERs and CRYs appears to be regulated by NAD.

In another bit of odd fate, the production of NAD is controlled by the circadian cycle, while the availability of NAD drives the circadian cycle. Seems a little inbreed, as well as a set up for failure. Regardless, having enough NAD
is crucial.

SIRT1 and 6 control the activity of all four of the protein groups mentioned above. The take-home message here is that the loss of circadian rhythms with age is controlled by a combination of the decline in the sirtuin family in conjunction with the declining concentrations of available NAD.

“Loss of SIRT1 in the brain not only regulates the circadian clock but also accelerates the aging process, which is most likely mediated by NAD.”

The loss of sleep, a misery unto itself, is not the only problem secondary to the disruption in the circadian cycle. Metabolism and insulin production are tied to circadian rhythms, which makes diabetes even worse with age. Disruption in the cycle is also known to contribute to cancer. Women that work nights and have disrupted sleep are more likely to get breast cancer, and unfortunately for us, the rate of aging is also accelerated with the breakdown of sleep patterns.

“Disruption of proper circadian timekeeping manifest in detrimental system effects and a number of clues from the clinic and laboratory suggest that these disturbances result in metabolic disruptions, cancer and age-related phenotypes.”

Another extremely important aspect of cellular control is the ability to affect cell division. In order to create a new cell, the mother cell must first replicate everything within itself, including its DNA and important organelles. These line up at the cells equator and then split evenly (hopefully) into two pieces. This cell division process is called mitosis and occurs a zillion times daily in your body. Without activation of the sirtuins, however, the daily turnover of cells would be hampered; and without new cells, you aren’t going to live very long.

Many of the sirtuins have also been identified as epigenetic regulators. As a reminder, epigenetic regulation is a system that controls what DNA sequences are physically available. This regulation can occur through DNA and/or histone modification.

Sirt2 has, for example, been identified as a histone modifier; more specifically a histone deacetylase. This is when an acetyl group is removed from a particular histone. Sirt2 effects H4 K16, meaning it modifies the acetyl group from histone #4 at the 16th lysine residue. Sirt6, meanwhile, acts at H3K9. By removing acetyl groups and changing the configuration of the DNA, the sirtuins serve as on/off switches.

Most of the proteins produced by the SIRT genes are deacetylases, i.e., they remove an acetylate group from a lysine amino acid within a protein. (Thus they are mediator genes) Exceptions are SIRT4, which has only ADP-ribosyltransferase activity and SIRT5 which had demalonylase and desuccinylase activity.

Whereas it certainly isn’t necessary to know exactly what histone is effected in these processes, I think this type of information elevates the concept from the theoretical realm into a more concrete, metabolic intervention. As well, the proximity of the histone gives researchers an idea of what genes are being affected to further the course of study. But I digress; that is not our issue.

Regardless, this control is known to affect the key elements necessary for mitosis, which takes us back to the idea of cell division. SIRT2 contributes to the manipulation of tubulin proteins, which are tiny threads or tubes that push and pull stuff around the cell in order to get the cell ready for division. Think of all the little organelles like puppets having little strings attached. Thus without SIRT2, cell replication would be compromised, and, since NOT aging relies on the continual process of cell replication and renewal, this is a key mechanism.

My particular favorite thing about the sirtuin family, however, is that several of them are able to preserve telomeric length.

If you remember from the DNA chapter, telomeres are repeating sequences at the ends of the nuclear DNA that serve as protector caps. There is, in fact as we mentioned before, a strong correlation between length of life and length of telomeres. Therefore, anything that promotes telomere length has to be good. SIRT6, acting through histone deacetylation mechanisms as well, seems to be central to this phenomena, but admittedly, details are scarce.

Continuing on why sirtuins are good for your DNA, the last thing to note is that SIRT1 and 6 are important in the control of DNA repair. We are now very aware that DNA gets damaged over time, so the repair mechanisms are crucial for survival. Also, remember that NAD is a necessary cofactor for DNA repair as it gets taken apart and physically placed into the holes as a patch. So NAD not only works in conjunction to drive DNA repair through the sirtuins, it is also used as a substrate to do the repairs themselves. Again, NAD is key to longevity.

SIRT1 also is known to trigger AMP Kinase. You already are experts on AMP Kinase, however, so I’ll keep going.

Sirtuins additionally help to regulate the immune system, and as we well know (or will soon enough), chronic inflammation stemming from an out of control immune system is a huge problem in aging.

SIRT1 and 6 inhibit the Nuclear Factor (NF-κβ) system, which sits at the top of the inflammatory cascade. Thus, activation of this family decreases almost all of the inflammatory factors.

We haven’t said anything yet about SIRT3, so let’s have a look.

Researchers at UC Berkeley and Harvard have studied SIRT3 extensively in the mitochondria of hematopoietic stem cells. It turns out that the expression of Sirt3 proteins declines 70% from young to old mice cells. As well, the functionality of the proteins diminish by about 30%. This isn’t surprising; it seems that all useful things tend to decay with time.

They found that if you increase the expression of Sirt3 proteins in young mice, nothing happens. However, if you precipitate an increase in the Sirt3 proteins in old mice, many things happen- really good things! The production of superoxide dismutase increases, as well as its actual activity; this, in turn, reduces the mitochondrial oxidative stress. In the words of the researchers: “the more surprising finding of our study is that up-regulation of SIRT3 rescues functional defects of aged HSC’s (stem cells) and that oxidative stress-induced physiological stem cell aging and tissue degeneration are reversible.” Thus, SIRT3 is particularly key to mitochondrial homeostasis as we age.

One last interesting tidbit: SIRT1 controls the accumulation of white adipose (fat) tissue that accumulates with age.

The less sirtuin proteins, the more the fat accumulates. Upregulation of Sirt1 in lab mice reduced fat storage, even when fed a high-fat diet. This, in part, explains the abdominal tire syndrome that is so common in the human middle agers. Of note, abdominal fat emits more inflammatory factors than regular fat. Luckily these can be blocked by the sirtuins as well.

Do sirtuins really play an actual role in life improvement? It certainly seems like they should! In lab mice that had overexpression or extra Sirt1 and Sirt6, their lives were extended. As well, and maybe more importantly, they seemed to have overall better health. The mice demonstrated more physical activity, had improved muscle mitochondrial function and slept better.

On the other side of the coin, mice that had less expressed sirtuins looked terrible and lived shorter lives. They had significant skin thinning, hair loss and reduced cellular regeneration.

So, after all of the research, I think it has become pretty well accepted that the sirtuin family is essential in the aging process. Unfortunately, as we all know, all of the sirtuin proteins decline with age, and thus, all of the age protecting mechanisms disappear with them.

Of course, this all won’t be worth mentioning if there wasn’t something we could do to boost our own SIRT activity.

Can anything increase sirtuins? Of course. Exercise is a key sirtuin enhancer, but I promised, this is not a book about exercise.

Caloric restriction also helps – feel free to starve yourself.

The best news, however, is that there are readily available substances that are known to activate the sirtuin family. Of these, resveratrol is the most famous and it comes from red wine. But alas, there are many others as well! Stay tuned.

3. The Third Marker Of Aging: mTOR

Our third pathway of note is the mTOR system, and it is quite different from the first two. In fact, it actually seems to be in direct opposition. The mTOR pathway is essential for growth and development when you are young.

However, as we get older, we just don’t need it very much anymore. Unfortunately, the body just forgets to turn it off.

But I’m getting ahead of myself. Let’s start from the beginning.

The story of the mTOR pathway begins, oddly enough, on Easter Island, thousands of miles out in the Pacific Ocean in the 1970s. In a soil sample taken in close proximity to one of the statues on Rapa Nui (the local name for the Polynesian Island), scientists identified a new anti-fungal agent and named it after the island, i.e., rapamycin. Isolated from Streptomycin hygroscopic, rapamycin has since been studied intensively for its immunosuppressant activity. The drug was approved in 1999 for use in post-organ transplant immunosuppression and is still used today.

Since then, this compound and several of its derivatives have been approved for a variety of medical uses including the prevention of stenosis after angioplasty (the ballooning open of arteries), as a treatment for some cancers, and to treat autoimmune diseases. As interesting as this is, of course, this is not the reason we are talking about rapamycin.

While researching this medication, it turns out, scientists discovered a whole body signaling system that controlled cell metabolism, growth, cellular proliferation and survival. As you have determined by now, the naming system in science is terrible and uninspired, thus the name for this pathway became the “Mammalian or Mechanistic Target of Rapamycin”.

mTOR is a serine/threonine protein kinase, thus it’s an enzyme in the mediator family.

This signaling pathway, much like AMP Kinase and the sirtuins, is influential throughout the body, affecting both intra and extracellular signals. It, as well, senses the environment, specifically amino acid availability, growth factors, insulin, energy status, oxygen levels and cellular stresses. In response, mTOR promotes anabolic processes; it builds things.

mTOR is essential to the biosynthesis of proteins, lipids, and organelles. This pathway is key to the growth and development of all cells and tissues, especially during the youthful periods of life. As a child and into young adulthood, growth is extremely important; in fact, I like to consider this system the pathway of youth.

At this time, the metabolism of cells is high, cells grow and multiply, and new blood vessels are created to provide nutrients to the new areas. This is called angiogenesis – think of new roads being built to supply new housing developments.

Unfortunately, as the body grows older, the need for unbridled growth is no longer important, and actually becomes detrimental. In fact, the pathway becomes obsolescent to a certain degree. It has been described as “an unintended and purposeless continuation of developmental programs which are not switched off upon their completion.” Oddly enough, as the useful substances in the body decrease with age, the not so useful ones seem to increase, and so, mTOR activity, especially mTOR signaling in the hypothalamic neurons, increases in an age-dependent fashion.

Let’s examine a typical cell and see why this becomes a problem.

In its youth, a cell sprints along doing it’s thing; producing proteins and new cellular elements, dividing, communicating – it's like a multi-tasking teenager.

As the inputs or activating stimulants start to decline, the cell starts to slow down. It still works, but it certainly doesn’t need to divide any more. This is called “Cell Cycle arrest,” meaning the cell stays in the same stage of life. It is equivalent to upper to middle life- the cell goes to work, does its job, doesn’t complain, isn’t partying all night and is generally content.

Unfortunately, mTOR does not want to leave these cells alone; the cells would love to revert to being more productive, but they cannot. The older cells simply do not have the capacity to respond the way they could before. As a result, these cells get pushed into what is called cell senescence. While these cells cannot divide, they begin to physically expand, and overproduce whatever it is they were producing in the first place. The cells thus first become hyper-functional; homeostasis is altered, and age-related diseases begin to appear. Ultimately, they start producing inflammatory factors and begin inflicting damage to the organism.

Increased blood pressure, for example, is partially the result of the hyper-functioning of smooth muscle cells within the arteries. Platelets, responsible for the formation of clots when you are bleeding, become hypercoagulable and cause clots when they shouldn’t. This can cause heart attacks and strokes.

Osteoporosis is the result of overzealous osteoclasts in the bone (osteoclasts destroy bone while osteoblasts rebuild bone…more on this later). Further examples include hyperglycemia, increased resistance to hormones, and higher circulating inflammatory factors. As time passes, these processes eventually lead to cell death, organ and tissue death and then organismal decline.

Autophagy is another key concept we need to discuss.

We will talk about this more in detail later, but for now here are the basics.

The word means exactly what it seems to, “self-consuming or to eat oneself.” This is an intracellular process where damaged organelles and unwanted molecules get broken down and recycled to make new ones. Removing damaged parts and pieces within a cell is crucial. Otherwise, cells end up looking like garbage depots or junk drawers, and cannot function as they need to. The other key purpose of autophagy is increasing the availability of nutrients when primary resources are scarce, i.e., it makes sense to recycle a broken mitochondria to make a new one. On the other hand, if nutrients are plentiful, the old mitochondria is left to rot and a new one is produced to take over its job.

mTOR prevails in times of high nutrient availability. Thus, it has no use for recycling. Activation of mTOR, therefore, blocks the process of autophagy. Conversely, blocking mTOR facilitates autophagy.

Research has demonstrated that blocking the mTOR pathway is good for longevity. This has been shown to be valid in yeast, nematodes, fruit flies, and mice. Blocking mTOR also seems to have some of the features of caloric restriction and in fact, dietary restriction has been demonstrated to reduce mTOR. This makes sense if you think about it. If there are fewer calories to burn, the body should be conserving them and not actively growing. Along a similar vein, the activation of AMP Kinase, which occurs when nutrients are low, inhibits mTOR as well.

Blocking mTOR not only has theoretical advantages in longevity, it has also been shown to improve healthspan. In mice rapamycin studies, spontaneous tumors and cancers were significantly reduced. In addition, age-related declines such as changes in heart function, liver and adrenal function and endometrial changes occur much more slowly in mice treated with mTOR blockers.

As the keynote blocker of mTOR, rapamycin had been studied extensively and does some pretty incredible things. In innumerable studies to date in mice and rodents, rapamycin has conclusively elongated lifespan.

The details of such include the following (see here, and here):

• There is a delay in the loss of stem cell function. This is useful as tissues that require high cell turn over, like blood or skin cells, can make new cells for a longer period of time before pooping out
• Delay in cognitive decline
• Delay in onset of retinopathy
• Delayed heart failure
• Delayed liver degeneration
• Delayed endometrial hyperplasia
• Less tendon stiffening
• Less decline in physical activity
• Cancer prevention (being used at present for Renal Cell Carcinoma)

All of these things are amazing and obviously what we all desire. Which, unfortunately, brings us to the saddest part of this journey; rapamycin comes with some terrible side effects.

For one, the drug is an immunosuppressant. That means that the risk of getting infections is extremely high. Mice and rats living in very clean laboratories don’t usually have this as an issue, but as actual people, this would be a real problem.

• Renal transplant patients on the medication report edema (swelling) (60%) and aphthous ulcers (55%)
• Ninety percent of people lose their hair (alopecia), and most report other hair and nail problems
• Men lose testicular function and fertility

In addition to these issues, there are a host of metabolic changes as well, such as:

• Hyperlipidemia
• Decreased insulin sensitive
• Glucose intolerance
• New onset diabetes
• Diarrhea

Based on this list, it seems unlikely that normal people are going to sign up for this treatment. On a redeeming note, because I can’t leave a chapter on a depressing bit of information, there is some good news. Metformin (glucophage), a drug we have mentioned briefly, acting through the activation of AMP Kinase can help to depress the levels of mTOR.

It’s not the perfect answer, but I’m sure we will find one eventually.

Summary: