March 2021

Biohacking, BLOG, Health Optimization, Human Optimization

MITOCHONDRIAL DYSFUNCTION: Our Powerhouse Gone Awry

Mitochondria serve as the powerhouses of our cells for which a delicate balance of energy flow is needed to generate energy production. Mitochondrial function has a substantial impact on the aging process and its dysfunction can accelerate aging.

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The biological definition of aging is the many processes of cellular damage accumulation in the body. These are known in the scientific literature as the Nine Hallmarks of Aging. We’ve covered the first four, or primary, hallmarks: genomic instability, telomere attrition, epigenetic alterations, and loss of proteostasis, as well as the first of the antagonistic: deregulated nutrient-sensing.

The role of the antagonistic hallmarks is to respond to and block the damage caused by the primary hallmarks. Yet, when bodily conditions become chronic and/or aggravated, they end up contributing to cellular damage and can accelerate aging. The sixth hallmark, and second of the antagonistic, is mitochondrial dysfunction. It is implicated in numerous age-related pathologies including neurodegenerative and cardiovascular disorders, diabetes, obesity and cancer.

Our source of cellular energy

You may remember from biology class that mitochondria are membrane-bound organelles, or specialized structures, within the cytoplasm our cells. Their main role is to metabolize, or break down carbohydrates and fatty acids, which creates energy-harvesting chemical reactions that result in adenosine triphosphate (ATP), often referred to as the energy currency of our cells. Mitochondria generate over 80% of our ATP through a process called cellular respiration, which requires oxygen. It does this via the oxidation of glucose.

Division, fusion and quality control

Mitochondria are highly dynamic and continually fuse and divide. Many cellular pathways allow this to happen, and these roles are critical, especially when cells encounter stress.

Mitochondrial fission, or division, is crucial to create new mitochondria for growing cells. Fission also contributes to quality control by enabling the removal of damaged mitochondria and can facilitate apoptosis (controlled cell death) during high levels of cellular stress. Mitochondrial fusion helps mitigate stress by mixing the contents of partially damaged mitochondria.

A 2017 research article in the journal, Genes, states that, “The maintenance of mitochondrial and cellular homeostasis requires a tight regulation and coordination between generation of new and removal of damaged mitochondria.” When these mechanisms are disrupted, it affects normal development, which can lead to neurodegenerative diseases.

Mutations

Mitochondria contain their own DNA (called mtDNA), separate from the rest of the genes in the nucleus of our cells. It is for this reason that some researchers believe that mitochondria evolved from primitive bacteria that developed a symbiotic relationship with our cells over 1.45 billion years ago!

One of the causes of mitochondrial dysfunction is mutations in mtDNA, which occur mostly due to spontaneous errors during the replication process and damage repair. As we age, these mutations have been shown to increase in the human brain, heart, skeletal muscles and liver tissues.

Energy and oxygen

In electron transport chain, a cluster of proteins transfer electrons through a membrane within mitochondria, which releases energy that is used to form an electrochemical gradient that drives the creation of adenosine triphosphate (ATP). Without enough ATP, cells are not able to function properly, and, after a long enough period of time, may even die.

Unfortunately during the process, mitochondria also produce most of the free radicals, or as scientists like to call them: reactive oxygen species (ROS). Mitochondrial dysfunction is mediated by several processes including increased production of ROS. Until recently, some researchers believed that ROS were the main cause of aging. However, studies have shown that purposely lowering ROS did not have a negative effect on health and that in fact, increasing ROS could be helpful in signaling cellular stress. Regardless, the increased production of ROS can contribute to a loss of mitochondrial integrity and biogenesis.

SOURCE: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748716/, Licensee MDPI, Basel, Switzerland.

Mitochondria are capable of self-replication, but progressively become more dysfunctional with age. They have built in quality control and housekeeping, but over time, these fail. As shown in the figure above from a research article in the journal, Genes, mitochondrial fusion and fission, a defective mitophagy process, and mitochondrial damage from increased mtDNA mutations, increased free radicals and oxidative damage and reduced ATP levels all contribute to age-related disorders associated with mitochondrial dysfunction.

How to improve mitochondrial function

While the jury is still out on exactly how to improve mitochondrial function and there is some controversy over some of the recommended treatments, there is agreement on a few ways to mediate mitochondrial dysfunction as we age.

A moderate level of eustress, or beneficial stress, has been shown to promote cellular and mitochondrial health. A concept named mitohormesis has been studied, which could promote lifespan and healthspan. A 2014 research article reviewed over 500 publications and found that, “Increasing evidence indicates. . .reactive oxygen species (ROS), consisting of superoxide, hydrogen peroxide, and multiple others, do not only cause oxidative stress, but rather may function as signaling molecules that promote health by preventing or delaying a number of chronic diseases, and ultimately extend lifespan.

“While high levels of ROS are generally accepted to cause cellular damage and to promote aging, low levels of these may rather improve systemic defense mechanisms by inducing an adaptive response.” Many call this the Goldilocks Zone – not too little, not too much. You may find a theme after reading our last few blogs: Calorie restriction and physical activity are two of the most substantial ways to maintain this balance.

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More about The Institute for Human Optimization

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2021-03-29/0 Comments/by Anil Bajnath

Biohacking, BLOG, Health Optimization, Human Optimization

DEREGULATED NUTRIENT-SENSING – A Fine Line Between Longevity and Aging

The capacity of our bodies to sense and respond to the ebb and flow of nutrient levels is vital to sustaining life. As we age, our body shifts in how its cells respond to the number of nutrients available.

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The biological definition of aging is the many processes of cellular damage accumulation in the body. These are known in the scientific literature as the Nine Hallmarks of Aging. We’ve covered the first four or primary, hallmarks already: genomic instability, telomere attrition, epigenetic alterations, and loss of proteostasis.

The next three hallmarks of aging are called antagonistic. Their role is to respond to and block the damage caused by the primary hallmarks. Yet, when bodily conditions become chronic and/or aggravated, they end up contributing to cellular damage, and thus accelerated aging.

The fifth hallmark, and first of the antagonistic, is deregulated nutrient-sensing. Our bodies contain complex regulatory mechanisms that measure nutrient scarcity or abundance. This process tells our cells whether to grow or whether to clean up and repair. This is based on the information it gets from hormone and protein signaling pathways.

The body’s balancing act

Metabolism is every biochemical reaction that goes on in your body. It converts food into the energy that sustains life, and there are specific proteins in the body that cause these reactions. When it comes to eating, your body uses a never-ending cycle that breaks down nutrients in food, rebuilds them, and then breaks them down again.

Energy is required for anabolism, or constructive metabolism, which is the process that builds new cells, maintains body tissues, and stores energy for later use. When your body is in an anabolic state, special enzymes separate the smaller molecules in your food, such as amino acids and glucose. These compounds are absorbed into the blood and carried to the cells, where they are either stored in body tissues such as the liver, muscles, and body fat or used for energy.

Energy is released during catabolism, or destructive metabolism, which is the process that generates the energy needed for all other cellular activities, including repair. When your body is in a catabolic state, it breaks down those complex molecules in order to release the energy you need for fuel. This then feeds the cycle that enables anabolism to begin again.

Building it up

We have evolved to be able to transition between anabolic and catabolic states, which has allowed us to survive and grow in environments in which nutrient availability is variable. One of the ways that our bodies do this is a signaling pathway controlled by a protein kinase, or enzyme, called mTOR.

mTOR controls cell growth, movement, and survival, as well as protein synthesis, autophagy, and transcription (how a cell copies its information when it’s ready to divide). It is adaptable and coordinates cell activity based on cues from the environment, such as nutrients, or lack thereof, and growth factors. It is ultimately responsible for the sensing of high amino acids concentrations.

Insulin-like growth factor-1 (IGF-1) primarily works with growth hormones to promote development in bone and tissues. IGF-1 uses the same signaling pathway as insulin, which tells the cells that glucose is present. This is known as the “insulin and IGF-1 signaling” (IIS) pathway, which is the most conserved age-controlling pathway throughout evolution. The IIS pathway regulates metabolism, growth, tissue maintenance, and reproduction in response to nutrient abundance.

When nutrients are abundant, the mTOR and IIS pathways work in tandem to form a network that helps to keep the body in an anabolic state that promotes cell growth and building. Conversely, mTOR is inhibited when nutrients are limited, which puts the body in a catabolic state and allows for cellular clean-up and repair.

Breaking it down

You may remember from a former blog that adenosine monophosphate-activated protein kinase (AMPK) acts like the body’s cellular housekeeper. It is what inhibits mTOR to promote catabolism. AMPK senses low energy states by detecting high AMP levels. AMP (adenosine monophosphate) is the end product of energy production.

Sirtuins are a family of proteins that regulate cellular health and they’re made by almost every cell in the body. They only function properly in the presence of nicotinamide adenine dinucleotide (NAD+), which is an essential cofactor in the production of energy by the mitochondria inside the cell and in energy metabolism.

Together, AMPK and sirtuins signal nutrient scarcity and catabolism. AMPK boosts NAD+, which in turn activates sirtuins. This initiates autophagy and the cellular housekeeping process begins.

You are what you do AND don’t eat

Sirtuins, mTOR, and the IIS pathway are all connected and respond to nutrient availability. One major way is via AMPK, and when it is activated, it prompts a cascade of complex interactions. Their functions fluctuate depending on the metabolic state of our body at any given time, thus their being labeled as part of the antagonistic hallmark of aging: deregulated nutrient-sensing.

Lopez-Ortiz et al concluded in their landmark paper, The Hallmarks of Aging, “Collectively, current available evidence strongly supports the idea that anabolic signaling accelerates aging, and decreased nutrient signaling extends longevity.”

Dietary restriction (DR), such as intermittent fasting or the fasting-mimicking diet, is the only intervention that has consistently been shown to increase lifespan. While we are still learning exactly why and how this is the case, the above-referenced research is showing that the sensing of nutrients plays an important part. We know that part of the reason dietary restriction works is by obstructing mTOR and the IIS pathway and activating AMPK and therefore sirtuins.

In our blog on autophagy, we explained that intermittent fasting means becoming conscious of the times you choose to eat and increasing the time you’re not consuming calories. It is also known as time-restricted eating. Valter Longo, Director of the Longevity Research Institute, helped popularize what he calls the fasting-mimicking diet. His research showed that mice that fasted intermittently had improved life spans, reduced inflammation, increased cognitive ability, and that this mechanism could be used in humans for similar results.

Dietary restriction is an effective way to increase your lifespan and your healthspan. It has been proven, and while it takes a lifestyle adjustment, it is possible for your choices to have a direct impact on how you age.