by Siim Land
Exposure to cold stress before heat stress lowers FOXO translocation in fruit flies but it doesn’t compromise longevity and resistance to the heat[91]. Cold exposure actually can boost longevity and lifespan.
FOXO3a is activated in response to hypoxic stress and inhibits apoptosis[92]. Hypoxia can be trained during exercise or some breathing methods.
The general trend for increasing FOXO follows the same pattern as the other longevity pathways such as AMPK and Sirtuins. Energy deprivation and adaptation to stress make the organism more resilient and longer lived. It forces the body to continue producing energy and survive in situations of low nutrients thus becoming really efficient at its own metabolic processes.
However, there’s a dichotomy between experiencing too much stress and getting just enough. Being chronically taxed out and under harsh conditions will inevitably lead to an accelerated deterioration just because of the accumulated damage. The cells themselves react to this by looking at the functioning of telomeres.
Telomeres and Longevity
The human body consists of trillions of cells and genes that compose the superorganism you are.
DNA molecules carry the genetic code that’s necessary for cellular growth, replication, and functioning of all living organisms.
Chromosomes are DNA molecules that contain the genetic material or genome of an organism.
Telomeres are nucleotide sequences at the ends of each chromosome that function as protective caps against deterioration.
The sequence of telomeres is TTAGGG, which gets replicated over 2500 times in humans. In Greek, telomeres are derived from ’telos’ (end) and ‘merοs’ (part). And they’re the tip of your genome.
Figure 14 Telomeres are protective caps at the ends of chromosomes
Telomeres were discovered in 1933 by an American cytogeneticist Barbara McClintock who saw that chromosomes without ending points became sticky and hypothesized there are some caps that help to maintain chromosome stability[93].
In 2009, Elizabeth Blackburn, Carol Greider, and Jack Szostak were given the Nobel Prize in Physiology or Medicine for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase[94].
In order to keep the organism alive, chromosomes are continuously replicating themselves and repairing DNA. Every bout of chromosome duplication causes a shortening in telomeres because the enzymes involved in duplicating DNA can’t continue their duplication all the way to the end of a chromosome. So, telomeres are vital protective caps that are supposed to protect the genes from damage during this process. They’re expendable, basically...
Telomere shortening prevents cells from replicating themselves by limiting the number of cell divisions. Shortened telomeres also weaken the immune system, increasing the risk of cancer[95]. Many age-related diseases are linked to shortened telomeres[96]. Longer telomeres are linked to longer lifespans than shorter telomeres[97]. Whether or not short telomeres are just a sign of cellular aging or the main contributors to the aging process is still unknown. Probably both.
On average, human telomeres shorten from about 11 kilobases as a newborn[98] to less than 4 kilobases in old age[99]. You lose more than half of your telomeres once you become older. However, your biological age can differ from your chronological age as your telomeres can either shorten or lengthen based on lifestyle factors.
Telomere length can be replenished by an enzyme called telomerase reverse transcriptase (TERT). TERT is a subunit of Telomerase which adds TTAGGG sequences to the ends of chromosomes[100].
Telomerase activity can prevent the shortening of telomeres that occurs with aging. Telomerase is responsible for the self-renewal properties of stem cells by elongating the telomeres of stem cells, which prevent telomere shortening and increase the lifespan of stem cells[101].
Telomerase is more active in rapidly dividing cells such as embryonic stem cells and adult stem cells and they’re quite low in neuronal, skin, pancreas, adrenal, cortex, kidney and mesenchymal stem cells.
In embryonic stem cells, telomerase is constantly active and thus maintaining telomere length and making the cell almost immortal.
However, most stem cells in the body don’t have enough telomerase to prevent telomere shortening and thus they’re still subject to aging albeit at a slower rate than in regular somatic cells[102].
Telomerase activity determines how many times a cell can divide before it dies off completely. It takes about 30-50 cycles of replication until the cell becomes senescent and dead.
Although telomere shortening is linked to aging, over-expression of TERT can promote cancer and tumor formation[103]. Telomerase activity can immortalize cancer cells[104] and about 90% of cancers are characterized by increased telomere activity[105]. This is probably due to the all-encompassing anabolic effects of cellular growth caused by the main growth pathway in the body mTOR that will grow healthy cells but unfortunately sustains cancerous cells as well if they’re already present.
Telomeres are highly susceptible to oxidative stress and stress-mediated DNA damage is a huge contributing factor to telomere shortening[106].
Too much stress shortens telomeres but it also damages the mitochondria. That’s why a healthy lifestyle should include active stress management. Here’s how to increase telomere length and prevent telomere shortening:
Meditation helps to maintain telomere length and protect them from getting damaged[107]. It increases telomere activity and reduces oxidative stress[108]. Meditating lowers psychological as well as physiological stress and boosts the immune system[109] – it creates emotional resiliency against all types of stressors thus promoting lifespan.
Telomeres and fasting are also quite tied with each other. Intermittent fasting can promote telomere activity and function through several mechanisms. It lowers oxidative stress, removes senescent cells through autophagy, and boosts stem cell production.
Resistance training and muscle building slow down aging. As you age you decrease the number of satellite cells that are precursors to skeletal muscle cells and you lose muscle mass. Shortening of satellite cell telomeres prevents satellite cell replication and contributes to age-related sarcopenia[110]. Chapter VII is dedicated to longevity-oriented exercise.
Frequent exercise may lower oxidative stress and protect telomeres from reactive oxygen species (ROS)[111]. ROS are detrimental in large amounts but they can actually make your body stronger in the right dose by the principle of hormesis. Chronic stress leads to oxidative stress and reduced longevity.
Hormesis and Longevity
From an evolutionary perspective, all of these pathways evolved the way they did as to promote the survival of the organism under harsh conditions. The vast majority of history on Earth has been governed by caloric deprivation, environmental challenges, and energy restriction.
It’s actually the „norm“ to be deprived and in a conserved state as to survive the fray so to say. Such adaptation would’ve allowed species to enter into metabolic states that promote a longer lifespan.
The biological phenomenon to this is called ’HORMESIS’, which comes from the Greek word hórmēsis and it means ‘rapid motion, eagerness’ or ‘to set in motion.’
Basically, hormesis is a biphasic response to a toxin or a stressor. (1) The initial contact causes injury to the body. (2) The following reaction leads to adaptation, leaving the body in a better condition than it was before.
Hormesis was first described by a German pharmacologist named Hugo Schulz in the year 1888. He discovered that a very small dose of lethal poison didn’t kill off the yeast he was experimenting with but actually made them grow. The term ‘hormesis’ itself was coined and first used in a scientific paper by Chester M. Southam and J. Ehrlich in 1943 in the journal Phytopathology (Volume 33, pp. 517-541).
In 2012, Mark Mattson explained that cells respond to bioenergetic stressors by increasing DNA repair proteins, antioxidant enzymes and the production of neurotrophic factors (such as BDNF)[112][113][114]. It’s
also believed that this is the reason eating vegetables, tea or coffee can improve brain health.
Plants contain 'noxious' chemicals that are supposed 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.
Friedrich Nietzsche said: “That which does not kill us makes us stronger.” He was a philosopher, not a biologist, but his quote aligns with the principles of hormesis perfectly.
Examples of Hormesis
Physical Exercise is a great example of hormesis. People with low levels of physical activity are said to be more prone to oxidative stress – not working out makes you more susceptible to a variety of diseases. How crazy is that? Exercise itself causes oxidative stress, especially at high intensities, like lifting weights or HIIT cardio. However, it triggers adaptations that increase mitochondrial density and biogenesis through mitochondrial hormesis.
Alcohol is another hypothetical form of hormesis as it’s believed to prevent heart disease and stroke. However, there’s evidence to show that these benefits are exaggerated. I would say that maybe a shot of vodka or a glass of wine once a week can be good for you but when you start drinking anything beyond that then you’re probably just lying to yourself – „Ahhh, got to get my hormesis in“ and you end up drinking every day. Beer, ciders, long drinks, cocktails they’re all anti-hormetic with zero advantages, like zero. You’re only killing your brain cells and getting fatty liver disease. That's why I've chosen to go no alcohol because there are no significant benefits to it.
Red wine contains resveratrol, which is one of those protective plant compounds and it’s greatly associated with anti-aging effects. Maybe 1-2 glasses of red wine a week can be beneficial but, again, I wouldn’t suggest drinking every day because alcohol is still a neurotoxin that directly damages nerve cells.
Exposure to Sunlight at low or moderate doses has a lot of health benefits. It’s one of the most effective ways of synthesizing Vitamin D in the body but it also supports most metabolic processes. In my opinion, this is somewhat of an underappreciated form of hormesis as many people have developed a fear of the sun.
Cold Exposure triggers AMPK, which causes your mitochondria to grow and improve their efficiency. It’s also a positive adaptation to lower temperatures with many other health benefits, such as reduced inflammation, stronger immune system, and greater tolerance to pain. All these things train the body to do more with less.
Heat Exposure activates these so-called ’heat shock proteins’, which allow the cells to resist the damaging effect of heat. High temperatures can also stimulate the lymphatic system, which works like an inner pump for moving liquids and toxins in the body.
Caloric Restriction and Intermittent Fasting cause mild oxidative stress that trigger protective sirtuin proteins. Short-term fasting and starvation can also fight cancer and make cancer patients more resilient against chemotherapy.
Mental Stress is another example of hormesis where you’re forced to flex your neural muscles. Learning new things, gaining skills, being in unpredictable high-stress situations, novel environments and challenges all trigger neuroplasticity and neurogenesis that make you grow new brain cells and create new synaptic connections. This actually bolsters your brain for future stressors and teaches you how to deal with them better mentally.
Whenever you’re in difficult situations or whenever you’re going through tough times in your life, then reminding yourself that it’s okay – that this pain will make me stronger in the future – then you’ll not only find more strength to deal with the present moment, but you’ll also augment your mindset for anything else that’s to come.
There’s the quote: “Pain is inevitable. Suffering is optional.” Which means that you can’t escape the physical stimuli – the pain, the discomfort, the emotions – but you can change your perception of it. Your perception of the things that are happening to you quite literally alter the way you experience and feel them. You’re using your mind to cause a different response, which is just powerful.
The Price of Longevity
There are also reasons to think that increased longevity will have tradeoffs in reproduction or other performance-related functioning. However, the tradeoff theory has been found to be inconsistent in research:
Guppies who live in nature grow and reproduce faster because of predatory pressures than guppies without natural predators. When predators are removed, these same guppies will still go and have more offspring and live longer[115].
Fruit fly mutants that live longer have even more progeny than normally[116].
Removing germline precursors in C. Elegans extends their lifespan[117]. This is not due to sterility but because of hormonal signaling of the DAF-16/FOXO pathway that localizes DAF-16 in the adipose tissue.
Humans can also suffer hormonal downregulation and low thyroid functioning with excessive caloric restriction and chronic stress. The goal is to stay above that threshold and incorporate enough balance.
There’s also the idea that stimulating growth with mTOR and IGF-1 will accelerate aging because of the growth mechanisms. However, there are as many reasons to think that inadequate levels of these pathways are as detrimental for longevity.
mTOR helps to build muscle and prevents muscle wasting, which is increasingly more important as you get older[118].
IGF-1 and mTOR increase bone density and joint strength, especially in cartilage and tendons.
Both high and low levels of IGF-1 are associated with increased mortality in a U-shape curve manner[119].
IGF-1 fights autoimmune disorders by increasing T-cells[120] and supports proper growth.
IGF-1 improves blood sugar regulation. Lower IGF-1 is associated with metabolic syndrome and insulin resistance[121]. This may be partly due to low insulin sensitivity that can be improved by building more muscle and stimulating mTOR.
Therefore, it’s not all black and white with longevity and these pathways. This book seeks to optimize all of these mechanisms we’ve been talking about.
Chapter II
The Hedonic Treadmill
“A nation is born stoic and dies epicurean”
Will Durant
Modern society is completely bizarre compared to what wild animals experience. Humans have undergone a massive change in our surroundings and habitat. If you’re reading this, then you’re probably quite well off. At least in comparison to what our species faced in the past.
The world in which we live isn’t perfect and devoid of all suffering but, in my opinion, it’s still better than ever before. Of course, our dangers may be much more threatening, such as nuclear explosions and global epidemics, but the majority of people are quite fortunate. However, this affluence comes at a cost, especially in wealthier countries.
Paradoxically, the richer the country the more health problems it tends to face. Diseases of the Civilization as they’re called are more predominant amongst upper-middle to high-income populations.
The issue isn’t just about being obese or diabetic. The problem is that in the rise of civilization’s comfort and abundance, we’re teaching ourselves to lose some of the positive qualities of human nature. Too many suffer from poor self-control, bad dietary habits, horrible biomarkers, and the general hedonic attitude towards life.
Figure 15 Rates of Obesity in the World
In an environment where food is more scarce and harder to come by, the situation would be slightly different. People either have to expend a lot more energy to get their calories or they simply wouldn’t be able to consume them excessively. That’s definitely not the only contributing factor to why richer societies tend to suffer from diseases but the correlation is easy to see.
Will Durant, a famous 20th-century historian said: “A nation is born Stoic and dies Epicurean”. Stoicism is a branch of Hellenistic philosophy t
hat emphasizes personal ethics, logic, and virtuous living whereas Epicureanism places pleasure as the greatest good. When you look at history, then it’s so true. Great civilizations of the past like Ancient Greece, Rome, Mesopotamia, the French Monarchy of Louis XIV all fell into the trap of excess glamour and comfort. As the people became wealthier, they became softer and thus more vulnerable to foreign invaders or upheavals. They became the victims of their own hedonic downfall.
As we know, the lessons of history tend to repeat themselves and human nature is very stubborn and resistant to change. That’s why it’s so important to create these situations of deliberate discomfort and voluntary challenges that elicit a hormetic response. Otherwise, you’d pre-dispose yourself to not only metabolic disorders but you’d be less capable to face unpredictable events in the future. In fact, it can be said that facing adversity, overcoming obstacles, and experiencing suffering is an essential component to having a meaningful human experience.
I’m not saying we should fabricate unnecessary pain in our lives. Instead, those uncomfortable and adverse situations help us to put things into perspective. They also contribute to our longevity through hormesis. Think of it as the Dauer state in larva who exponentially extend their lifespan just because of being put under environmental pressure. I know the resemblance isn’t easy to accept but that’s the general principle of stress adaptation.
Hedonic Adaptation
It's funny to be talking about such things in the first chapters of a nutrition book but I think it’s very important. The more exposure you get to any stimuli, the more resistant you become towards it. Let's take insulin resistance as an example.