How to
Introduction
When you think of aging, what comes to mind? Do you picture yourself crushing it like you are today, or do you imagine wheelchairs and medicine cabinets stuffed with pill bottles? You might assume that you’re destined for the latter. But, it doesn’t have to be that way.
One of my big goals is to age well. After all, who wouldn’t want to live to be 100-years-old—or more? Research shows that you can be an active participant in your own aging process.
While the average life expectancy for Americans is 78 years and Indians is 70 years, your habits and your environment have a lot of influence on your longevity, and how you’ll do life in your later years.
Here are some things you can do and follow to start to age not just gracefully, but powerfully: the latest science shows that if you work on the aging process, you can take on your further years with enough mobility, energy, and mental clarity to enjoy them.
We Have More Control Over Aging Than We Think
But isn’t longevity hereditary? you might ask.
While our lifespan is partially influenced by our genetics, it’s really only a small part, or about 25% [Ref. 1].
Consider that life expectancy worldwide has increased by around fifteen years in the last fifty years. Human genes haven’t change but our environments and lifestyles have. Advances in medicine have been able to eradicate deaths from many diseases. Now, I’ll talk about ways we can improve longevity further. (In this article I am only talking about mTOR pathway, although the IIS, AMP-K, and sirtuin pathways also influence aging.)
[1] Human longevity: Genetics or Lifestyle? It takes two to tango, University of Calabria https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822264/
The Biology of Aging — An Overview
Figure 1: Factors related to aging [Ref. 1]
[1] The Hallmarks of Aging, University College London https://www.cell.com/fulltext/S0092-8674(13)00645-4
Place your cursor over/click each factor for the explanation.
DNA damage accumulates with age. We can slow aging by encouraging DNA repair and the elimination of damaged cells.
Telomere, the ends of chromosomes, shorten with age. DNA polymerase Telomerase repairs this damage. Therefore activating telomerase could slow aging.
Epigenetic changes affect all cells and tissues throughout life. They are modifications to the physical structure of DNA that regulate whether genes are turned on or off. These modifications are chemical compounds that attach to DNA (epigenome) but do not change the sequence of DNA building blocks. Therefore unlike DNA mutations, epigenetic alterations are reversable.
Manupilating the epigenome postively impacts the packaging of DNA, gene regulation & expression, promoting DNA repair and slowing aging. Histone modification is a type of epigenetic alteration. Sirtuins enzymes affect this histone modification. Therefore enhancement in sirtuin activity can slow aging.
Proteostasis is a balanced state when production of proteins is stable and without defects. The protein system achieves that by maintaining the correct structural form of proteins and by digesting and recyling unwanted proteins (autophagy). Errors in the protein system disturb proteostasis resulting in the aggregation of misfoled proteins which play a key role in age-related diseases.
Interventions improving proteostasis can slow aging.
When calories (energy from nutrients) are not available our bodies adjust by lowering insulin and IGF1 levels slowing the regeneration and reproduction of new cells. Instead the body diverts energy into cellular processes that protect the cells we already have: it produces more enzymes to ensure proteins don't misfold and digests old proteins, it ramps up the machinery designed to repair broken DNA and it breaks down cellular debris and defective cells it might otherwise ignore. Therefore calorie restriction slows aging, and a similar benefit could be achieved by decreasing the nutrient sensing & signalling ability of the body so that the cellular machinery behaves as it would when calories are not available.
In addition to the IIS (Insulin and IGF1) pathway that senses glucose, three other nutrient sensing pathways impact aging. mTOR for sensing high amino acids concentrations, AMPK which senses low energy/calorie level by detecting high AMP levels, and Sirtuins which sense low energy/calorie level by detecting high NAD+ levels. Inhibiting IIS and mTOR, and activating AMPK and Sirtuins slows aging. This can be achieved by biological stressors like dietary restrictions.
As we age our bodies are less effective at removing dysfunctional and damaged cells. These Senescent cells stop multiplying but don't die when they should. They linger and harm neighboring cells releasing chemicals that trigger inflammation.
Clearing senescent cells can slow aging.
Stem cells provide new cells to our body and replace damaged cells, playing a key role in the repair and regenration of damaged tissue and organs.
Stem cell function declines with age as a result of multiple types of aging-associated damages.
We can slow aging by rejuvenating old stem cells.
Hormesis: what doesn’t kill you makes you stronger
Hormesis is defined as a “beneficial effect caused by exposure to low doses of an agent known to be toxic at higher doses.” [Ref. 2]
Friedrich Nietzsche said, “That which does not kill us makes us stronger.” He was a philosopher, not a biologist, but his quote fits hormesis perfectly.
However, the devil’s in the details: if the dose or the duration of the biological stressor is too intense, then there will be a net negative impact on the body instead.
Multiple beneficial responses that help slow aging
Step 1:
When exposed to mild stress, cells respond by a variety of adaptive cellular programs. One such beneficial hormetic response is autophagy increase and mTOR inhibition.
Step 2:
After the mild stress is removed the cells achieve a preconditioned and adapted state.
Step 3:
When experiencing intense stress these preconditioned cells exhibit stress resistance and eventually improved survival.
Basically, hormesis is a biphasic response to a toxin or a stressor. The small stimulus leads to a net adaptation, leaving the body in a better condition than it was before. There are many different types biological stressors, and many of them may be familiar to you as healthy practices:
Fasting
Please check articles on Fasting.
Exercise
Please check articles on Exercise.
Heat and cold exposure
Please check article on Cold Therapy.
Ultraviolet Sunlight
Sun exposure also triggers hormesis. UV rays cause sunburn, cancer, and all kinds of nasty damage if you get too many of them, but when you get the right dose, sun exposure is an incredibly powerful technique. For example, sunlight in the right, controlled dose actually protects against cancer [Ref. 5].
Please check article on Sunlight.
Consuming lots of different plants (xenohormesis)
Plants contain ‘noxious’ chemicals to protect them from being eaten by insects and other organisms. However, thanks to the constant evolutionary arms race between us and animal kingdom, we’ve developed counter-adaptations in the form of hormesis and we trigger a beneficial response when eating these foods [Ref. 6].
[2] Hormesis, ScienceDirect https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/hormesis
[3] Healthy Effects of Plant Polyphenols: Molecular Mechanisms, University of Massachusetts Amherst https://www.mdpi.com/1422-0067/21/4/1250
[4] When less is more: hormesis against stress and disease, Université Paris Descartes https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354599/
[5] Xenohormesis: health benefits from an eon of plant stress response evolution, Wake Forest University School of Medicine https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024065/
[6] Sunlight and Reduced Risk of Cancer: Is The Real Story Vitamin D?, Vanderbilt University https://academic.oup.com/jnci/article/97/3/161/2544132
Cold-shock and Heat-shock Proteins
Intense and brief hot or cold exposures both trigger a cascade of positive changes in the body. The secret to these benefits lies in shock proteins. Your body produces these proteins, appropriately named cold-shock proteins [Ref. 7] and heat-shock proteins [Ref. 8], in response to sudden, extreme changes in temperature.
When cells experience stress, they activate cold-shock proteins which begin to regulate gene expression. The benefits of cold shock proteins include:
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Therapeutic cold therapy can help with neurodegenerative disease by suppressing neuronal apoptosis (death of neurons) and inflammation. [Ref. 9]
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Cold increases adiponectin, which is a protein that helps with blood sugar regulation [Ref. 10]
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Winter swimming lowers uric acid and increases glutathione, an enzyme that promotes detoxification and the body’s antioxidant sytem [Ref. 11]
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Cold activates brown adipose tissue, which improves mitochondrial functioning, metabolism, and thermoregulation [Ref. 12]
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Increases the CARHSP1 enzyme that binds to and stabilizes tumor necrosis factor alpha (TNF–α), reducing inflammation in the body. [Ref. 13]
What can you do? Spending time in cold environments and doing cold baths can stimulate these beneficial effects.
[7] Cold-shock response and cold-shock proteins, Robert Wood Johnson Medical School https://www.sciencedirect.com/science/article/abs/pii/S1369527499800319
[8] Heat Shock Proteins, University of Oldenburg https://link.springer.com/chapter/10.1007/978-0-387-39954-6_1
[9] Cold Shock as a Possible Remedy for Neurodegenerative Disease, University of Tsukuba https://clinmedjournals.org/articles/ijnn/international-journal-of-neurology-and-neurotherapy-ijnn-3-053.php?jid=ijnn
[10] Cold exposure increases adiponectin levels in men, University of Ottawa https://www.ncbi.nlm.nih.gov/pubmed/19303978
[11] Uric acid and glutathione levels during short-term whole body cold exposure, Humboldt University https://pubmed.ncbi.nlm.nih.gov/8063192/
[12] Cold-Activated Brown Adipose Tissue in Healthy Men, Maastricht University Medical Center https://www.nejm.org/doi/full/10.1056/nejmoa0808718
[13] CARHSP1 is required for effective tumor necrosis factor alpha mRNA stabilization and localizes to processing bodies and exosomes, Veterans Health Administration Medical Center https://pubmed.ncbi.nlm.nih.gov/21078874/
Reduce mTOR and Increase Autophagy
Mechanistic Target of Rapamycin (mTOR) is a protein kinase fuel sensor that monitors the energy stats of your cells; it responds to signals from nutrients, growth factors, and cellular energy status and controls cell growth and proliferation based on this (by regulating protein synthesis). It’s involved in every aspect of cellular life and existence.
In simpler terms, whenever we have lots of nutrition (mainly protein) and calories, we essentially tell the body that plentiful times are here. mTOR is the protein that “senses” this, and signals our cells to increase their working capacity and ATP (energy) production. Cells also divide and reproduce faster, which primes the body for rapid growth and repair. However, in times of stress such as reduced caloric or nutrient intake, mTOR activity decreases (is inhibited) [Ref. 14].
Figure 14: A simplified version of mTOR [Ref. 15]
To stay healthy, mTOR must be cycled. Sometimes we want to increase it to grow muscle and improve certain aspects of cognition, while the rest of the time want to have low levels to increase longevity, decrease cancer risk, and reduce inflammation. You see, mTOR increases energy production, but also creates more junk products.
A few diseases associated with mTOR activation [Ref. 16]:
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Aging
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Cancer
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Autoimmune disease
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Diabetes
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Obesity
Autophagy is the natural, conserved degradation and recycling of unnecessary or dysfunctional cell components. Autophagy is very important, but it is only active when mTOR is decreased. In other words, the body doesn’t start cleaning up until the party is over. Autophagy is equivalent to a ‘detox’ from a scientific perspective. And we need a balance between growth/junk products (mTOR) and rest/clean up (autophagy).
A few inhibitors of mTOR / promoters of autophagy [Ref. 17] [Ref. 18]:
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Intermittent fasting
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Exercise
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Omega-3 fats (in fish & seafood)
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Ketogenic diets
[14] Updates of mTOR inhibitors, Louisiana State University Health Sciences Center https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2980558/
[15] Dysfunction of the mTOR pathway is a risk factor for Alzheimer’s disease, Newcastle University https://actaneurocomms.biomedcentral.com/articles/10.1186/2051-5960-1-3
[16] mTOR is a key modulator of ageing and age-related disease, University of Washington https://www.nature.com/articles/nature11861
[17] The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway, Washington University School of Medicine https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076631/
[18] mTOR and the health benefits of exercise, University of California Davis https://www.sciencedirect.com/science/article/abs/pii/S1084952114002535
References
[1] Human longevity: Genetics or Lifestyle? It takes two to tango, University of Calabria https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822264/
[2] Hormesis, ScienceDirect https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/hormesis
[3] Healthy Effects of Plant Polyphenols: Molecular Mechanisms, University of Massachusetts Amherst https://www.mdpi.com/1422-0067/21/4/1250
[4] Xenohormesis: health benefits from an eon of plant stress response evolution, Wake Forest University School of Medicine https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024065/
[5] Cold-shock response and cold-shock proteins, Robert Wood Johnson Medical School https://www.sciencedirect.com/science/article/abs/pii/S1369527499800319
[6] Heat Shock Proteins, University of Oldenburg https://link.springer.com/chapter/10.1007/978-0-387-39954-6_1
[7] Cold Shock Proteins and Autophagy https://siimland.com/cold-shock-proteins-and-autophagy/
[8] Cold Shock as a Possible Remedy for Neurodegenerative Disease, University of Tsukuba https://clinmedjournals.org/articles/ijnn/international-journal-of-neurology-and-neurotherapy-ijnn-3-053.php?jid=ijnn
[9] Cold exposure increases adiponectin levels in men, University of Ottawa https://www.ncbi.nlm.nih.gov/pubmed/19303978
[10] Uric acid and glutathione levels during short-term whole body cold exposure, Humboldt University https://pubmed.ncbi.nlm.nih.gov/8063192/
[11] Cold-Activated Brown Adipose Tissue in Healthy Men, Maastricht University Medical Center https://www.nejm.org/doi/full/10.1056/nejmoa0808718
[12] CARHSP1 is required for effective tumor necrosis factor alpha mRNA stabilization and localizes to processing bodies and exosomes, Veterans Health Administration Medical Center https://pubmed.ncbi.nlm.nih.gov/21078874/
[13] Sunlight and Reduced Risk of Cancer: Is The Real Story Vitamin D?, Vanderbilt University https://academic.oup.com/jnci/article/97/3/161/2544132
[14] Updates of mTOR inhibitors, Louisiana State University Health Sciences Center https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2980558/
[15] Dysfunction of the mTOR pathway is a risk factor for Alzheimer’s disease, Newcastle University https://actaneurocomms.biomedcentral.com/articles/10.1186/2051-5960-1-3
[16] mTOR is a key modulator of ageing and age-related disease, University of Washington https://www.nature.com/articles/nature11861
[17] The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway, Washington University School of Medicine https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076631/
[18] mTOR and the health benefits of exercise, University of California Davis https://www.sciencedirect.com/science/article/abs/pii/S1084952114002535
Do you use any positive stressors to make yourself more resilient? What’s your favorite technique to stay young? I want to hear about it in the comments. Thanks for reading, and don’t forget to subscribe for more health and longevity content.