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Cell Chatter: The Critical Role of Cell Signaling in Aging, Part 2

Cell chatter has an indispensable role in essential inter-cell communication, and the quality of the signal, if you will, impacts the aging process via the Hallmarks of Aging and age-related diseases.

Cell chatter is a colloquial way to say that the trillions of cells that make up our body have their own language. That language is often referred to as “cellular signaling pathways”. They play critical roles in regulating various aspects of cellular function and can interact with the multiple aging hallmarks reviewd in Part 1 of this three-part series, either positively or negatively.

The interactions between these pathways and hallmarks are complex and often interconnected, and their dysregulation can contribute to the aging process and age-related diseases. Maintaining a balance in these pathways through lifestyle choices and interventions can be essential for promoting healthy aging.

And that’s why I’m wrirting this post, and why it’s in your best interest to dig in.

 

A primer on cell chatter

Cell chatter via signaling pathways enable cells to communicate with each other to keep everything in check and running as smoothly as possible. Think of them as the texting system of our cells.

Those trillions of cells that make up our body need to keep in touch in order to work properly. It’s as if your body is a large, busy city with trillions of cells going about their business. And just like in a city, communication is key. Cells need to talk to each other to coordinate tasks, share information, and respond to changes. That’s the job of these signaling pathways – they’re like a bunch of text messages zipping around, keeping everyone in the loop.

But these pathways aren’t just about everyday tasks. They also have major roles in the story of aging.

It’s very obvious that as we get older, our bodies start showing certain signs – things like wrinkles, slower movements, aches and pains. We covered what’s behind these and many other telltale signs of aging in the lesson about the Hallmarks of Aging.

As you’ve learned in Part 1, the Hallmarks of Aging are a set of fundamental biological processes and characteristics that underlie the aging process and contribute to age-related decline in health and function, eventually leading to the development of age-related diseases.

We now turn to the cell chatter that play a critical role in interconnecting and influencing the various aging hallmarks.

These pathways act as communication networks within cells; they are intricate messengers that guide our cells’ essential functions, allowing them to respond to internal and external signals. They have a critical role in overseeing a variety of cellular tasks, from DNA repair and metabolism to inflammation and stress response, and given this, they can have a profound impact on the progression and interaction of aging-related processes.

Dysregulation of these pathways — meaning, when these cellular signaling pathways become compromised, and are not working properly — can accelerate the aging process and contribute to age-related diseases. It’s also true that if any of these cellular signaling pathways are over or under expressed, our health will become compromised.

And so, we want to understand and target these pathways with interventions that not only promote healthy aging, but also prevent age-related diseases, which will be the topic of Part 3 next week.

 

Cell chatter to the Hallmarks of Aging

The aging hallmarks are like a checklist of what’s happening inside our cells as time goes by. You will recall that they include things like changes in our DNA, problems with how our cells produce energy, and even issues with the way our immune system responds. It’s like this bustling metropolis that is our body and its biochemical systems are getting worn down, and the signs are popping up everywhere.

The cellular signaling pathways are the links between these signs of aging and what’s happening inside our cells. It’s as if these pathways are the translators, taking the “cell language” of the hallmarks and turning it into action. When one hallmark starts acting up, it sends a message through these pathways, causing a chain reaction that affects other hallmarks.

All this cell chatter works behind the scenes, making sure everything goes according to plan – or sometimes, not according to plan. When these pathways misinterpret messages or go haywire, that’s when things start to get complicated. It’s like the city’s communication system is breaking down, and chaos happens.

One important key to maximizing healthspan involves finding a balance between the activation and inhibition of various cellular signaling pathways. Striking this balance is essential for maintaining cellular and tissue health, preventing age-related diseases, and promoting healthy longevity.

There are many cellular signaling pathways, but I want to cover seven prominent ones that appear to have an overly large role in the aging process.

The seven are:

1. mTOR (mechanistic target of rapamycin)
2. AMPK (AMP-activated protein kinase)
3. IGF-1 (Insulin-like Growth Factor-1)
4. Sirtuins (SIRT1 thru SIRT7)
5. FOXO (Forkhead Box O proteins)
6. p53 (Tumor protein P53)
7. NF-kB (Nuclear Factor-kappa B)

mTOR

mTOR (mechanistic target of rapamycin) plays a significant role in regulating lifespan, aging, and age-related diseases. It’s involved in multiple Hallmarks of Aging, including deregulated nutrient sensing, mitochondrial dysfunction, compromised autophagy, and altered intercellular communication.

The mTOR signaling pathway acts as a vital conductor in the symphony of cellular activities, governing growth, metabolism, and responses to nutrients and stress.

When conditions are favorable, mTOR springs to life, spurred by signals like nutrient intake, especially amino acids. This prompts cells to grow, proteins to be synthesized and nutrients to be absorbed.

But under unfavorable circumstances like nutrient scarcity or stress, mTOR retreats — it gets downregulated — and energy is conserved to maintain survival.

As concerns aging, mTOR is a double-edged sword. While necessary for growth and repair, chronic mTOR activity can contribute to age-related troubles. For instance, chronic mTOR activation fuels cellular senescence, which if you remember from Part 1 is a state of irreversible growth arrest that fosters inflammation and tissue dysfunction. mTOR can also hinder autophagy, impairing the cell’s ability to rid itself of damaged internal components. And chronic mTOR activation potentially contributes to metabolic glitches like insulin resistance seen in many age-related diseases.

mTOR fuels cellular senescence
mTOR impairs autophagy
mTOR can promote metabolic dysfunction

The tightrope to walk here is to skillfully orchestrate mTOR’s activation and deactivation in order to strike a harmonious balance. Doing this has the potential to influence healthy aging and possibly extend lifespan, as it has in every animal cohort studied, such as worms, flies and mice [1][2][3], with a dog study underway.

The bottom line is that you want to modulate mTOR so that it’s activated enough to repair and build your body, such as your muscles as you strive to keep sarcopenia at bay, which is muscle wasting, while deactivating mTOR when it’s not needed. For instance, to activate mTOR when performing exercises that break down muscle tissue, such as resistance training and high intensity interval training, and to deactivate it otherwise.

Sarcopenia is the age-related progressive loss of muscle mass and strength.

mTOR activators/deactivators:

• Activators: High amino acid levels (esp. leucine), high glucose levels, growth factors (e.g., insulin, IGF-1).
• Deactivators: Caloric restriction, fasting, rapamycin (drug), exercise.

Relevance to Aging Hallmarks:

• Promotes protein synthesis and cell growth.
• Inhibits autophagy

Interaction with Aging Hallmarks:

• Contributes to the loss of proteostasis (protein homeostasis) by promoting protein synthesis and inhibiting autophagy.
• Can influence cellular senescence, stem cell exhaustion, and genomic instability by regulating cell growth and division.

AMPK

AMPK (AMP-activated protein kinase) is a cellular energy sensor that regulates metabolism and cellular homeostasis.

Imagine AMPK as the energy manager of your cells, constantly checking the fuel gauge. It activates when cellular energy levels are low, often due to exercise or nutrient scarcity. This activation prompts cells to conserve energy and promote cellular maintenance by enhancing processes like autophagy, which is a process that clears out cellular debris.

AMPK also dampens mTOR activity, slowing down growth and protein synthesis. It’s like a cellular financial advisor, helping cells make smart energy investments for the long term.

This interplay between AMPK and mTOR is important — they have opposite effects that must be managed in order to maximize healthspan.

For instance, mTOR is like a switch that promotes growth and building things in your body. This can be good for making muscles and repairing tissue, but if mTOR is always switched on, it might lead to issues like excessive cell growth and aging-related problems.

AMPK, on the other hand, is a switch with a near-opposite effect than mTOR has, one that helps your body save energy and tidy up. When it’s activated, it encourages your cells to use energy wisely and keeps things clean inside. This can be beneficial for your overall health and lifespan.

The key is finding the right balance between these switches. Keeping mTOR in check, so it’s not always on, in part by not eating certain amino acids throughout the day, such as leucine, can help prevent excessive growth and aging-related issues. Activating AMPK by exercising and sometimes fasting can encourage energy conservation and help your cells stay healthy.

The bottom line is that you want to activate AMPK when mTOR is deactivated, and a good time to do that is to activate AMPK when you’re not in a post-exercise anabolic state (muscle feeding).

AMPK activators/deactivators:

• Activators: Reduced energy intake (TRE, CR, fasting), exercise, drugs metformin, some dietary compounds (ALCAR, berberine, EGCG).
• Deactivators: High ATP levels, high glucose levels.

TRE is time-restricted eating, a type of intermittent fast.
CR is caloric restriction.
ALCAR is acetyl-L-carnitine, a synthesized version of L-Carnitine.EGCG is Epigallocatechin gallate, a polyphenol found in green tea.
ATP is adenosine triphosphate (ATP). Often referred to as the "molecular unit of currency" of intracellular energy transfer, it’s an organic compound that provides energy to drive and support many processes in living cells.
IGF-1 is Insulin-like Growth Factor-1), a hormone involved in cell growth, survival, and metabolism. Its role as a growth promoter in cells is often activated by growth hormone.

Relevance to Aging Hallmarks:

• Regulates energy balance.
• Activates autophagy and mitochondrial biogenesis.

Interaction with Aging Hallmarks:

• Supports mitochondrial function, which impacts mitochondrial dysfunction.
• Activates autophagy, addressing compromised macroautophagy.
• Plays a role in nutrient sensing and metabolic health, impacting deregulated nutrient sensing and metabolic derangement.

IGF-1

IGF-1 (Insulin-like Growth Factor-1) is involved in cell growth, survival, and metabolism. Its role as a growth promoter in cells is often activated by growth hormone.

When we’re young, IGF-1 promotes tissue growth, cell division, and protein synthesis; however, when we’re older, high IGF-1 levels may not always be beneficial. It gets back to balance, or homeostasis. While it can help with tissue repair, excessive IGF-1 activity may contribute to accelerated aging and diseases like cancer and neurodegenerative disorders.

It’s a bit like a gas pedal that needs to be controlled to avoid speeding into problems.

The bottom line is that you want to ensure that you have regular periods of IGF-1 deactivation; therefore, deactivate it when you’re not in a post-exercise anabolic state (muscle feeding).

IGF-1 activators/deactivators:

Activators: Nutrient-rich diets, GH release, high protein intake.
Deactivators: Caloric restriction, fasting.

GH is growth hormone, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals.

Relevance to Aging Hallmarks:

• Promotes cell growth and proliferation.

Interaction with Aging Hallmarks:

• Overactivity can contribute to aging hallmarks by promoting cellular growth and proliferation, potentially impacting genomic instability, cellular senescence, and stem cell exhaustion.

Sirtuins

Sirtuins are a group of enzymes that play critical roles in various cellular processes, including aging, metabolism, DNA repair, and stress response. There are seven known mammalian sirtuin proteins, SIRT1 through SIRT7, each with specific functions and cellular locations.

You want your sirtuins to be activated. As with AMPK, this happens in response to calorie restriction, and potentially by some compounds. When activated, sirtuins act like the regulators or supervisors that oversee various cellular processes, such as those just mentioned, and ensure they work properly.

The objective with sirtuins, then, is to activate them regularly when you’re not in a post-exercise anabolic state (muscle feeding).

Sirtuins activators/deactivators:

Activators: Caloric restriction, fasting, physical exercise, NMN, NR, curcumin, quercetin, EGCG, honokiol and glutamate.
Deactivators: High-calorie diets, sedentary lifestyle.

NMN is nicotinamide mononucleotide, a compound sold as a supplement as a precursor for NAD+, which is nicotinamide adenine dinucleotide, a critical coenzyme found in every cell in your body that's involved in hundreds of metabolic processes like cellular energy and mitochondrial health.
NR is nicotinamide riboside, a compound sold as a supplement as a precursor for NAD+.
EGCG is Epigallocatechin gallate, a polyphenol found in green tea.
ALCAR is Acetyl-L-carnitine, a synthesized version of L-Carnitine.

Relevance to Aging Hallmarks:

• Regulate epigenetic modifications and metabolic processes.

Interaction with Aging Hallmarks:

• May mitigate epigenetic alterations through deacetylation of histones.
• Influence mitochondrial function, affecting mitochondrial dysfunction.
• Impacts deregulated nutrient sensing and metabolic derangement by regulating metabolic processes.

FOXO

FOXO (Forkhead Box O proteins) play a crucial role in various cellular processes, including cell cycle regulation, DNA repair, antioxidant defense, and stress response. They are often associated with promoting longevity and protecting against age-related diseases.

FOXO proteins act as guardians of the cell’s health, patrolling for signs of stress and damage. They help cells adapt by regulating various genes involved in stress resistance, DNA repair, and antioxidant defenses.

As we age, FOXO activity can decline, reducing the cell’s ability to respond to stress. Think of them as vigilant security personnel, keeping a watchful eye on cellular well-being.

The objective with FOXO is to activate them regularly.

FOXO activators/deactivators:

Activators: Caloric restriction, intermittent fasting, exercise, antioxidants, polyphenols, sleep, stress reduction, plant-based diet.
Deactivators: Insulin signaling activation, growth factor stimulation.

Relevance to Aging Hallmarks:

• Regulate stress response and longevity genes.

Interaction with Aging Hallmarks:

• Promote antioxidant defense mechanisms and DNA repair, potentially impacting genomic instability.
• Influence cellular senescence, stem cell exhaustion, and altered intercellular communication by regulating stress response and cell cycle control.

p53

p53 is a protein that acts as a tumor suppressor, which means that it regulates cell division by keeping cells from growing and dividing (proliferating) too fast or in an uncontrolled way.

It primarily functions as a “guardian of the genome” by responding to DNA damage and various cellular stresses, such as oxidative stress. It’s involved in DNA repair, cell cycle arrest, and apoptosis. It plays a crucial role in maintaining genomic stability.

Apoptosis is the process of programmed cell death. In adults, apoptosis is used to rid the body of cells that have been damaged beyond repair, and also plays a role in preventing cancer.

You can imagine p53 as a cellular firefighter. When DNA damage or stress occurs, p53 springs into action, initiating repairs or even triggering cell death if the damage is too severe to fix.

It’s a crucial guardian against cancer, preventing the propagation of damaged cells. However, as we age, p53 can become overactive, potentially contributing to tissue dysfunction and aging-related diseases.

Because p53 activation primarily occurs in response to cellular stress and DNA damage, it’s not directly influenced by nutrients or lifestyle factors.

P53 activators/deactivators:

Activators: DNA damage, oxidative stress, cellular stress activate P53, which is supported by exercise, CR, sulforaphane compounds, EGCG, curcumin.
Deactivators: Inhibition by MDM2 protein, which is regulated by nutrient availability.

CR is caloric restriction.
Sulforaphane is a compound found in broccoli, cauliflower and cabbage.
EGCG is epigallocatechin gallate found in green tea.

Relevance to Aging Hallmarks:

• Acts as a tumor suppressor and regulates DNA repair.

Interaction with Aging Hallmarks:

• Can induce cell cycle arrest or apoptosis in response to DNA damage, affecting genomic instability and cellular senescence.

NF-kB

NF-kB (Nuclear Factor-kappa B) is a key regulator of inflammation and immune responses. NF-kB is like the cell’s emergency response team. It gets activated when there’s inflammation or stress, helping to initiate the immune response.

This however can become problematic if the activation is persistent, which is often seen with chronic inflammation, an aging hallmark. When this occurs, it can lead to tissue damage and aging-related diseases. It’s a bit like firefighters trying to control a blaze; when not managed properly, it can lead to collateral damage.

NF-kB activators/deactivators:

Activators: Inflammatory cytokines (e.g., TNF-α, IL-1), pathogen-associated molecular patterns (PAMPs), oxidative stress.
Deactivators: Anti-inflammatory compounds (e.g., curcumin, EGCG, quercetin, boswellia), antioxidants.

Relevance to Aging Hallmarks:

• Regulates inflammation and immune responses.

Interaction with Aging Hallmarks:

• Overactivity can lead to chronic inflammation, impacting several aging hallmarks, including chronic/systemic inflammation and cellular senescence.

 

Your Takeaway

I began this post by stressing that you need to strive for a balance in the regulation of these cellular signaling pathways. This is a key approach to maximize healthspan. I told you what activates and deactivates each of the seven pathways we covered, and touched on those you generally want to emphasize activating and those to deactivate in a modulating fashion.

Balancing cell chatter

Most people need to work on deactivating mTOR, IGF-1 and NK-kB simply because most of us are in caloric surplus, and many of those calories come from foods that promote the activation of these pathways, such as meat, processed foods, lack of exercise and dysregulated sleep.

So, the two things you need to do here is to:

1. Make the lifestyle changes I’ve indicated that can deactivate mTOR, IGF-1 and NK-kB; and
2. Make the lifestyle changes I’ve indicated that can activate AMPK, Sirtuins, FOXO and p53.

The following table provides a summary:

Cellular Pathway	What it Does	Modulation
— Modulation Focus: Deactivate —
mTOR IGF-1	Associated with cell growth, proliferation, and anabolism. Crucial for development and tissue repair, but chronic overactivation can have detrimental effects, like cancer, type 2 diabetes, neurodegenerative diseases, cardiovascular diseases, kidney diseases.	Caloric restriction, fasting, rapamycin (drug), exercise.
NK-kB	Involved in inflammation and immune responses. Essential for fighting infections and injury, but chronic activation can lead to chronic inflammation, a hallmark of aging and age-related diseases. Balancing NF-kB activity is important to regulate inflammation.	Anti-inflammatory compounds (e.g., curcumin, EGCG, quercetin, boswellia), antioxidants.
— Modulation Focus: Activate —
AMPK Sirtuins FOXO	Associated with cellular maintenance, repair, and stress response. Activation of these pathways can promote cellular resilience, repair damaged components, and support longevity. However, excessive activation may also have negative effects, so a balanced approach is necessary.	Reduced energy intake (TRE, CR, fasting), exercise, drugs metformin, some dietary compounds (ALCAR, berberine, EGCG). Caloric restriction, fasting, physical exercise, curcumin, quercetin, EGCG, honokiol and glutamate. Insulin signaling inhibition, oxidative stress, nutrient depletion, growth factor deprivation.
p53	Primarily functions as a “guardian of the genome” by responding to DNA damage and various cellular stresses, such as oxidative stress or oncogene activation.	DNA damage, oxidative stress, cellular stress activate P53, which is supported by exercise, CR, sulforaphane compounds, EGCG, curcumin.

Remember that the goal is not to completely inhibit these pathways, but rather to achieve a balanced and well-regulated activity to support health and longevity.

To do this you need to adopt the right lifestyle factors that involve diet, exercise, sleep and stress management, along with periodic challenges that activate hormesis.

Some hormetic stress is good

Hormesis is a very important concept to understand when it comes to healthy longevity. Hormesis is a biological phenomenon in which exposure to a low or moderate dose of a potentially harmful agent or stressor can stimulate adaptive responses in you that stimulate beneficial effects on health, resilience, and longevity. In other words, what doesn’t kill you may make you stronger, at least within certain limits.

A good example of hormesis is resistance training, such as weightlifting, an activity that results in microtears in the muscles used. Subjecting the body to this moderate physical stress triggers a series of adaptive responses that heals the tears, and makes the muscles stronger.

Aging hallmarks and disruptions in cell chatter contribute to the four most prominent chronic diseases associated with aging, often referred to as the Four Horsemen of Disease.

The Four Horsemen of Disease:

1. Atherosclerotic disease (comprised of cardiovascular [heart] and cerebrovascular diseases [brain])
2. Cancer
3. Neurodegenerative disease (Alzheimer’s the most common)
4. Metabolic disorders (a spectrum: hyperinsulinemia, insulin resistance, fatty liver disease, type 2 diabetes, obesity, etc.)

I will tell you about the Four Horsemen in Part 3, the final piece in this three-part series. Look for that next week, or subscribe to my newsletter to be alerted when I publish a post.

Go here for Part 1.

 

 

Last Updated on September 21, 2023 by Joe Garma