by Siim Land
Some species and bacteria can also be revived after thousands of years of hibernation. But there’s a difference between aging and immortality. Both of them are relevant for determining an organism’s lifespan.
The Hallmarks of Aging
In 2013, Lopez-Otin and colleagues published a review of the hallmarks of aging in different species including mammals[6]. They are:
Genomic Instability – genetic damage and mutations throughout life
Telomere Attrition – shortening of protective telomere caps on top of chromosomes that occurs during DNA repair
Epigenetic Alterations – alterations in methylation patterns, post-translational modification of histones, and chromatin remodeling
Loss of Proteostasis – dysfunctional protein folding, proteolysis, and proteotoxicity. Basically, not being able to put muscle back together correctly.
Deregulated Nutrient Sensing – inadequate growth hormone production, related to the Insulin/IGF-1 signaling pathway
Mitochondrial Dysfunction – old worn out mitochondria begin to produce more reactive oxygen species and oxidative stress, which damages all other cells
Cellular Senescence – the accumulation of dead cells and cancer proliferation
Stem Cell Exhaustion – decline in regenerative potential of tissues and lack of swapping old cells with new cells
Altered Intercellular Communication – miscommunication in endocrine, neuroendocrine, or neuronal systems that cause inflammation and other problems
There are many things that determine the lifespan of an organism, such as its genetics, phylogeny, mutations, and life history but the biggest role probably has to do with the ecological niche. What kind of an environment both internal and external the animal is living in and how it’s going to respond to it.
Biological organisms develop certain adaptations based on the conditions they get exposed to in their environment. That’s why some animals have completely different metabolic profiles as well as physical traits than humans. They also live differently partly because of how they’ve adapted to their surroundings over the course of eons. That’s why most of these hallmarks of aging are controllable and epigenetic. You can influence your rate of aging and longevity by simply understanding these mechanisms and changing your lifestyle.
Mitochondrial Theory of Aging
What causes death and aging has been a topic of inquiry amongst humans for eons. It’s often explained away by spiritual, religious, or purely physical reasons. But why does it happen?
In 1956, Denham Harman was the first to propose the Free Radical Theory of Aging (FRTA)[7] and furthered the idea in 1970 to describe mitochondrial production of reactive oxygen species (ROS)[8].
The free radical theory of aging states that organisms die because of the accumulation of free radical damage on the cells over time.
A free radical is an atom or molecule with a single unpaired electron in its outer layer. Most free radicals are very reactive and they cause oxidative damage. That oxidation can be lowered by antioxidants and other reducing agents.
Mitochondria are the cells’ energy manufacturers that generate adenosine triphosphate (ATP). It’s the energetic currency needed for life. This process occurs by reacting hydrocarbons from calories or sunlight with oxygen.
The classical free radical theory of aging proposes that energy generation by the mitochondria damages mitochondrial macromolecules, including mitochondrial DNA (mtDNA), which promotes aging[9]. After a certain threshold, this produces too many reactive oxygen species (ROS), which cause cell death and degradation.
Figure 3 Reactive Oxygen Species and Mitochondrial Aging
Mitochondrial Free Radical Theory of Aging was introduced in 1980, which implicate the mitochondria as the main targets of ROS damage[10]. This happens when electrons get out of the electron transport chain and react with water to create ROS, such as superoxide radical. These radicals damage DNA and other proteins.
Age-related impairments in the mitochondrial respiratory chain decrease ATP synthesis, damage DNA, and make the cells more susceptible to oxidative stress.
However, it’s been now shown that mutations in mtDNA can result in premature aging without increasing ROS production by mutating the polymerase Pol-γ that’s responsible for mitochondrial DNA synthesis[11].
There are many factors that affect lifespan. Excessive generation of ROS and mutations in mtDNA both are central to the mitochondrial theory of aging. However, it’s suggested that ROS aren’t the primary or initial cause of it.
Reactive Oxygen Species and Aging
The ability to cope with oxidative stress and other stressors is compromised in aging thus making you more vulnerable to free radicals as you get older. Mutant mtDNA increases with age, especially in tissues with higher energy demands like the heart, brain, liver, kidneys, etc. These notions support the theory of mitochondrial aging[12].
In some species like yeast and fruit flies, reducing oxidative stress can extend lifespan[13]. However, blocking the antioxidant system in mice doesn’t shorten lifespan in most cases[14]. Likewise, in roundworms, inhibiting the natural antioxidant superoxide dismutase has been shown to actually increase lifespan[15].
Taking a lot of antioxidants and lowering oxidative stress with supplements have failed to be effective in fighting disease and in fact may promote the chances of getting sick. Treatment with high doses of anti-oxidants like beta-carotene, vitamin A, and vitamin E may actually increase mortality[16]. Consuming more fruit and vegetables doesn’t seem to have a significant effect on reducing cancer risk[17].
Free radicals and ROS are involved in most human diseases and cancers but their degree of influence is still uncertain. Increasing your body’s own endogenous antioxidant levels may be a better option for disease prevention[18].
Oxidative stress and free radicals can increase life expectancy in nematodes by inducing a bi-phasic response to the stress. This phenomenon is called mitohormesis or mitochondrial hormesis.
Hormesis is a dose-specific response to a toxin or a stressor that makes the organism stronger than it was before (Figure 4). The idea is that you experience a small shock that makes the body want to deal with it better in the future thus becoming more resilient. Sublethal mitochondrial stress with a minute increase in ROS may cause a lot of the beneficial effects found in caloric restriction, intermittent fasting, exercise, and dietary phytonutrients[19].
If you experience no stress and zero exposure to free radicals, then your body is by default weaker because of having no fighting reference from the past.
If you experience too much stress and excessive accumulation of ROS, then you promote disease and sickness because of not having enough time to recover.
If you experience just the right dose of stress, then you’ll be able to deal with it, recover from the shock, and thus augment your cells against future stressors.
If you block all mitochondrial stress and eliminate free radicals, then your body won’t have the time nor the means to promote mitohormesis. That’s why antioxidants all the time won’t have a positive effect.
Figure 4 The Dose Matters for Hormesis
Mitochondrial decay is central to the mitochondrial theory of aging and it’s one of the major causes of aging.
Here are some of the factors that have been shown to produce oxidative stress and induce mitochondrial aging.
Insulin and high glucose environments generate free radicals and promote oxidative stress[20]. The insulin signaling pathway is one of the main mechanisms of accelerated aging. However, this is dose specific and some is beneficial for ROS production[21].
Chronic stress accelerates aging and disease. Over-production of free radicals due to excessive stress hormones decreases mitochondrial functioning and makes you more prone to disease because of a weakened immune system, high insulin, and damage to cells.
Sleep deprivation and circadian mismatches promote all disease. If your body’s biological clocks are misaligned with its circadi
an rhythms, then you’ll cause more cellular stress and predispose yourself to all types of dysfunctions.
Avoid environmental toxins and pollution. Polluted air, water, heavy metal exposure, mercury in food, pesticides, glyphosate, GMO crops, toxic personal care products, house cleaning chemicals – all of them will create more reactive oxygen species and oxidative stress. The amount of these stressors is beyond our body’s natural ability to cope with them, thus they don’t have a beneficial effect in the long run.
Avoid inflammation like wildfire. Inflammation is correlated with most diseases, as it directly decreases the body’s immune system. Processing food and over-cooking it increases the number of free radicals and carcinogens in it.
There’s a difference between beneficial stressors and too many free radicals. Of course, excessive oxidative stress is still bad for you and accelerates aging. The key is to differentiate it from the positive hormetic stress.
The mitochondria are one of the most important organelles in your body as they govern everything related to energy metabolism and cellular homeostasis. Dysfunctional mitochondria will not only speed up aging but also make you feel more tired, exhausted, lethargic, weak, and experience atrophy.
All of the ideas related to hormesis, mitohormesis, avoiding oxidative stress and getting the right amount of reactive oxygen species will be talked about in the upcoming chapters. Having covered this, I’m going to move on with the other related pathways and mechanisms that are shown to affect aging and longevity.
Longevity Pathways in Humans
Like said before, different individuals of the same species may exhibit drastically different life spans and rates of aging. This is so because aging is regulated by many genetic pathways and biological processes.
In humans, there are several longevity pathways recognized to control the aging process and its constituent mechanisms. I’m going to outline the ones that are currently most recognized to regulate longevity and lifespan. Then I’ll go through them one by one in closer detail.
The Growth Hormone/Insulin and Insulin-Like Growth Factor-1 Signaling Pathway, which regulates cell replication, nutrient partitioning, and storage.
The FOXO/Sirtuin Pathway, which includes proteins and transcription factors responsible for energy homeostasis. They manage homeostasis under harsh conditions and stress.
Hormesis and General Stress Adaptation mediated by FOXO proteins and mitochondrial functioning. This phenomenon makes the organism more resilient against environmental stressors.
The mTOR/AMPK Pathway, which governs homeostasis between anabolism and catabolism. Basically, it’s the body going to grow or eat itself.
All of these pathways interact with each other and they’re affecting longevity in different ways. These are the mechanisms that affect aging and lifespan. Let’s now walk through them in closer detail one by one.
The Insulin IGF-1 Pathway
One of the most well-known pathways of longevity is the Insulin/IGF-1 Signaling Pathway (IIS).
Insulin is the main storage hormone that directs nutrient partitioning and glycogen replenishment. It basically helps to unlock the cells so they could store glucose into liver and muscle glycogen.
Insulin-Like Growth Factor (IGF-1) or somatomedin C is an IGF-1 encoded human gene. It’s also been referred to as the ’sulfation factor’. IGF-1s role is to promote tissue growth and development.
The effects of IGF-1 are mediated through the IGF-1 receptor (IGF-1R), which is similar to the receptor of the storage hormone insulin.
IGF-1 gets produced in the liver by the stimulation of Human Growth Hormone (HGH). IGF binding protein (IGFBP) is a binding protein that carries IGF-1 around the body and it’s regulated by insulin.
Figure 5 The Effects of IGF-1 in the Body
Reduced insulin signaling has been found to increase the lifespan of fruit flies, nematodes, and rodents[22]. Here are some of the studies in other living organisms:
In 1993, it was discovered that mutating an insulin-like receptor called DAF-2 by suppressing it in nematodes doubled their lifespan[23]. This extension required the presence of another gene DAF-16, which encodes together with a FOXO transcription factor[24]. DAF-2 activates the signaling pathway of PI-3 kinase, which shortens lifespan by activating insulin/IGF-1 signaling and phosphorylating DAF-16[25]. Suppressing DAF-2 does the opposite. In humans, DAF-2 is the equivalent of IGF-1 and insulin signaling.
Reducing glucose and carbohydrate intake increases FOXO activity by suppressing insulin/IGF-1 signaling (IIS). One study done by Lee et al. found that adding just 2% of glucose into the diets of roundworms shortened their lifespan by 20% because of inhibiting the activity of DAF-16/FoxO and heat-shock factor HSF-1[26]. Not a good trade-off.
Insulin/IGF-1 receptor mutations can increase the lifespan of fruit flies by up to 85%[27]! Additionally, mutated suppression of an insulin receptor substrate (IRS)-like signaling protein called CHICO increases the lifespan of fruit flies by 48%[28]. This seems to be dependent on FOXO proteins, which are transcription factors of longevity. Drosophila dFOXO signaling controls lifespan and regulates insulin signaling in the brain and fat tissue[29].
Knocking out the IGF-1 receptor in mice makes them live 26-33% longer[30]. Mice who lack the insulin receptor in fat tissue live 18% longer[31].
In yeast, mutating the insulin-dependent AKT ortholog SCH9 triples their mean lifespan[32]. Additionally, overexpression of SIR2, which is part of the insulin/IGF-1 pathway in C. Elegans extends the lifespan of worms and yeast by up to 50%[33].
All these findings show that the insulin/IGF-1 system is a critical regulator of the organisms longevity by controlling many downstream pathways. They vary between species but their orthologs are found in humans as well.
We don’t have many human studies showing the same longevity benefits of limiting blood sugar and insulin. Animals in labs are also living in very controlled environments and we can’t tell what’s their subjective well-being like. The challenge in humans is not to mimic the long livest yeast diet but rather to find a way that helps us to eat less without unsustainable restriction.
Insulin/IGF-1 Signaling in Caenorhabditis Elegans
The Insulin/IGF-1 Signaling Pathway has been found to play a crucial role in the aging and development of lower organisms such as Caenorhabditis Elegans, nematodes, roundworms, and larva[34].
Nematodes go through several cycles of development during their average three-week lifespan. One of them is the Dauer stage that gets activated during periods of higher environmental stress[35] (Figure 6).
Figure 6 Notice how entering into the Dauer stage can extend the larva's life by several months.
Dauer larvae are morphologically specialized roundworms that adapt to harsh conditions such as starvation, temperature stress, and oxygen deprivation. Normally, they would exit the period of conservation according to the influx of energy from their environment, but this cycle can be prolonged in laboratories. Dauer larvae can survive up to 8 times longer under laboratory conditions[36]. That’s a huge difference based on a simple elongation of a certain life stage and environmental input.
In 1999, it was found that Sir2 overexpression in yeast extended their lifespan by 50%[37]. Sirtuin genes have been found to have similar anti-aging functions in other species, such as yeast, fruit flies, and roundworms[38].
Sirtuins are a family of proteins that act as metabolic sensors. They deacetylase the coenzyme NAD+ into free nicotinamide. Basically, they break down acetyl from proteins to maintain their functioning for longer. The ratio of NAD+ to NADH determine the nutritional status of the cell and sirtuins are there to respond.
NAD+ is an essential currency for energy metabolism and DNA repair. Sirtuins are proteins that evolved to respond to the availability of NAD+ in the body.
Figure 7 The Mechanisms of NAD+ and Sirtuins
SIRT6 overexpression has been found to lengthen the lifespan of male mice by as much as 15,8%[39]. SIRT6 deficiencies in mice accelerate their aging
[40]. This may be due to the anti-cancer effects of SIRT6, not the anti-aging itself.
Cellular deterioration and senescence are thought to be caused mostly by the accumulation of unrepairable DNA damage[41]. SIRT1 plays an important role in activating DNA repair proteins[42]. It’s specifically involved with repairing the double helix of DNA[43].
SIRT1 can also induce cellular autophagy by directly deacetylating AuTophaGy (ATG) proteins such as Atg5, Atg7, and Atg8[44]. This then promotes mitophagy or mitochondrial autophagy and helps to eliminate old worn out cells.
How to Increase Sirtuins for Longevity
There’s a lot of evidence pointing to the longevity benefits of increased sirtuin activity in humans as well. If not in over-expression, then increasing sirtuins can still be good for your health in most cases.
Glucose restriction extends the lifespan of human fibroblasts because of increased NAD+ and sirtuin activity[45]. Inhibiting insulin shuttles SIRT1 out of the cell’s nucleus into the cytoplasm.
Caloric restriction and fasting increase SIRT3 and deacetylate many mitochondrial proteins[46]. Reduction of calorie intake without causing malnutrition is the only known intervention that increases the lifespan of many species including primates[47][48]. It’s thought that these effects in longevity require SIRT1[49].
Activating AMPK elevates NAD+ levels, leading to increased SIRT1 activity[50]. AMPK is the fuel sensor that mobilizes the body’s energy stores such as fat and it promotes autophagy as well.
Ketosis and ketone bodies like beta-hydroxybutyrate (BHB) are associated with increased sirtuin activity. SIRT3 deficient mice can’t produce normal levels of ketones while fasting[51]. However, a ketogenic diet increases brown fat and improves mitochondrial function but lowers SIRT3 in mice[52]. This may be due to the signaling of mTOR by a nutrient-dense diet high in too much fat. While we now have all sort of ketogenic products like exogenous ketones and MCT oils, caloric restriction and fasting are still the best ways of signaling energy deprivation which promotes longevity. In an everyday context, a low carb diet is still pro-sirtuin to a certain extent because of the lower levels of blood glucose and less insulin due to that increased satiety that occurs with a lower carbohydrate diet. More about optimizing the macronutrient ratios in future chapters.