Duncan Carmichael, MD explores how our understanding of ageing has shifted over the years and impacted the ways we combat the process
I find it difficult to enjoy a social media platform nowadays without getting tripped up by some sincere appeal that swallowing vitamin X may help me live longer, or doing activity Y should make me healthier for longer. Once I have taken all this advice and swallowed the resveratrol to switch on healthy genes, the metformin to reduce insulin resistance, performed some high-intensity exercise to boost six health pathways, meditated to extend my telomere length, gotten eight good hours of sleep according to my Fitbit app, and sat in an ice bath to lower my core temperature, I may well have run out of time in the day to feed the kids and get to work.
The problem is that this advice can’t all be equally important and equally right; and when you think about it, one health article often gives completely opposing advice to another! For example, is it more important to exercise and switch on six pathways of health, or should we consider the opposite advice and meditate to slow our heart rate down to preserve us for longer?
The philosophies that give the structuring to all of this advice are known as the ‘theories of ageing’. So important are these pillars of thought that scientists have spent the last century arguing over the merits of the different theories. If we really want to know what we should be doing to optimise our lives, then before meditating or swallowing an antioxidant we first need to understand which of the underlying theories is the most important — or to plagiarise the author JRR Tolkien, which is ‘the one ring to rule them all?’ Once we can understand why a theory is important, we can confidently ignore other earnest appeals on social media and focus on the supplements and activities that will benefit us the most.
The first of the grand theories of ageing that we will look at was proposed by August Weismann nearly 140 years ago. At the time, he was seen as being almost as famous as Charles Darwin and a leader in biology and evolution. He proposed the first big explanation for why we age and called it the wear-and-tear theory: as horses age, they wear down their teeth and so have nothing left to chew with. We can’t deny that as we age our knee joints wear out, our teeth wear down, and our sight fails. Wear-and-tear is undoubtedly a significant part of the ageing process, but does it drive the ageing process? For many years this theory was accepted as the leading theory of ageing; however, as other theories surfaced, Weismann’s theory became understandably less popular.
The problem with the wear-and-tear theory was that there wasn’t much you could do about it — horses couldn’t exactly chew less in a bid to live a little longer. So, by the 1960s another much sexier theory had taken centre stage — the free radical theory.
I have Dr. Denham Harman to thank for the basket of antioxidant supplements that is accumulating dust in my kitchen cupboards. Up until the 1950s, the concept of free radicals and antioxidants was quite unknown. In 1954, when Dr. Harman proposed his free radical theory, no one took him seriously. But Harman was not only inquisitively intelligent, but also tenacious. Having been a scientist in the oil industry for many years, he went back to university at the relatively old age of 38 to study medicine. Instead of opting for a comfortable life in private practice, he became fascinated with ageing and went back into research. In 1954, when he proposed that elements called ‘free radicals’ bounced around our cells like unstable magnets causing them to age, and that ‘antioxidants’ prevented this damage, he was laughed out of the lecture hall. His entire life’s work seemed to have been in vain.
However other scientists then showed that when our cells make energy by mixing oxygen and glucose, they also create a free radical called superoxide. This is so damaging that every cell has an enzyme called superoxide dismutase (SOD) that acts as an antioxidant specifically to clear away all the damaging superoxide free radicals. Scientists then agreed that if it was so important for every cell to produce the antioxidant SOD, then free radicals must exist and Harman’s theory of free radical damage must be correct after all.
After many years of being ignored, Harman’s free radical theory became an overnight global hit. This was the big new theory of ageing: Studies came out to show that we accumulate free radical damage as we age1. Other studies show that antioxidants like vitamin C and A could be applied to the skin to reduce sun-induced DNA damage and skin cancer2. The more antioxidants we took, the quicker they would snuff out inflammation and prevent damage. In short order, the free radical theory became the most widely quoted theory of ageing. For 40 years the excitement regarding antioxidant supplements drove us all, and there was barely a bathroom cupboard that didn’t contain cod liver oil or high dose vitamin C to boost our health.
However, cracks started to show in the free radical theory:
- One would expect that if we removed our SOD antioxidant enzymes, then our cells would suffer huge damage. However, in a study on worms, those that had their SOD systems switched off did not die young as expected and some actually lived longer3. Perhaps antioxidant systems were not as vital as we had previously thought
- Vitamin supplements should help to prevent free radical damage inside of us and there is no finer example of free radical damage than the damage that cigarettes inflict on our lungs. However, in a study involving smokers, those who were given vitamin E supplementation had a higher chance of getting lung cancer than smokers who did not take the protective antioxidant4. How could protective antioxidants be contributing to premature death? It was theorised that excessive vitamin supplements could make our own internal antioxidant systems lazy and result in more damage than good. Up until now, this has yet to be proven5.
- However, what has been discovered is that:
- Excessive antioxidants can switch off our P-53 system. The P-53 system removes damaged or cancerous cells, so without it, cancer cells tend to proliferate6.
- When we exercise, we release free radicals that stimulate our own SOD antioxidant enzymes to switch on7.
- So, we know that free radicals damage us and that antioxidants protect us from this damage. However, the concern is that taking excessive antioxidants could switch off systems that are needed to remove damaged and cancerous cells.
Nearly 20 years after he came up with the free radical theory, Dr Harman had the final say on the topic: in a final roll of the dice to show the benefits of vitamins, Harman gave cancer-prone mice antioxidants in the hope that it would help them to live longer. They didn’t live longer and after that it was just a matter of time before other theories would start to claim the top spot in the race to be the leading theory of ageing8. Whichever theory came out on top would need to demonstrate what no previous theory had ever achieved — it would need to show that it could actually extend lifespan.
The mitochondrial theory of ageing
With the realisation that protecting our own intracellular antioxidants like SOD was more important than swallowing antioxidant vitamins, research swung to other intracellular organelles that might be important in ageing. At the top of the list was the mitochondrion. Your average cell can carry up to 2000 mitochondria, whose primary job is to take glucose and oxygen and convert them into ATP energy. If the mitochondria are not making energy, then we will feel exhausted. They are the engines of the cell and rather like when a car’s engine burns out and we discard the car, when the cell’s mitochondria burn out, the cell is also discarded.
One of the most important places for us to have healthy mitochondria is quite sensibly in our muscles. As we age, our muscles start to run out of healthy mitochondria and we can no longer run as far or as fast as we once could9. What is worse, once the mitochondria are damaged, just like an old engine billowing smoke, damaged mitochondria release free radicals, damaging the cells and accelerating early cell death10. As we start to age, the degeneration process can move surprisingly quickly and this is partially blamed on our fading mitochondria.
So scientists have been looking for ways to protect and rebuild our mitochondria not only to improve our health but also to extend life:
A big breakthrough came in the 1960s when scientists showed that exercise could restore healthy mitochondria and delay the ageing process11. With more healthy mitochondria in the cell, there was more energy, less free radical damage, and cells were expected to live longer. This translated into a better ‘healthspan’— elderly people had better energy and health. It did not pass the ultimate test as the exercise did not increase their ‘lifespan’ (the maximal number of years that we can live).
Research continued but by the millennium the initial enthusiasm and funding had faded from mitochondrial research.
However, there has been a recent discovery that might just bring mitochondrial research back into the big league. In 2016, vitamin B3 (nicotinamide) proved to be an exciting revelation for mitochondrial health. Nicotinamide is converted in the body to NMN (nicotinamide mononucleotide). NMN is the essential element to help mitochondria make ATP energy. Scientists showed that supplementing NMN to mice improved their mitochondrial energy resulting in weight loss and healthier, energised mice12. In a separate study in 2018, the famous Dr. David Sinclair showed that NMN supplementation improved mitochondrial functioning which actually rejuvenated the arteries and muscles of ageing rats13. Mitochondrial research may yet prove to be a central component in our battle against ageing.
By the 1970s, scientists started to suggest that we may possess ‘longevity genes’ (otherwise known as ‘gerontogenes’). These are genes that when switched on, could extend life longer than would be expected. Scientists suggested that specific longevity genes might be responsible for a 90-year-old looking and feeling healthy. It took until the 1980s for the first gerontogenes to be identified and this discovery caused a wave of excitement through the world of healthy ageing. At last, we had something that could potentially extend lifespan and this was bringing a lot of attention to the field:
- By the early 1990s, the scientist, Cynthia Kenyon stumbled across a gene called Daf-2, which when disabled could double the lifespan of worms14
- The sirtuin genes (affectionately known as SIR genes) are a class of genes that extend life either by being switched on or switched off. Scientists discovered that by switching on the SIR-2 gene, they could extend the lifespan of the humble yeast15
- Other genes followed suit with Daf-16, FOXO, and mTOR all showing their class in being able to extend lifespan.
The belief was that people could possess up to 11 different gerontogenes, but that only the lucky few express them, helping them to live long, healthy lives.
Attention then shifted to what lifestyle changes we could make to switch these genes on and could these changes be shown to extend life in us humans.
Scientists showed that by severely restricting calories, SIR-2 was activated in yeast cells and they lived longer. Next, David Sinclair (who we met earlier) caused great excitement when he showed that resveratrol (the antioxidant found in grapes and wine) was able to switch on the SIR-2 gene in worms and extend their lifespan16. We were one step closer to finding the first supplement that could be proven to extend life in humans.
However, it is one thing to show that a longevity gene has been switched on and quite another to show that this translates to a longer healthier life. Disappointingly, a large 2014 study showed that elderly people who supplemented with resveratrol (and had presumably switched on their SIR-2 gene) did not live any longer than people who had deficient levels of resveratrol17. We are going to have to do better than switch just one gene on and expect to live longer.
Gerontogene research is still in its infancy. Scientists are looking towards a remarkable technology called CRISPR, which bacteria use to cut out unwanted DNA and helps them evolve antibiotic resistance. They are hoping that one day we can swallow a capsule containing CRISPR technology that will chop out old genes and replace them with healthy gerontogenes.
Calorie restriction theory
Calorie restriction is currently the ‘One ring to rule them all’ – it is the most exciting theory in the world of healthy ageing. In the 1930s, when American researcher Clive McCay showed that rats who were fed a calorie-restricted diet lived longer than rats eating a normal diet, this theory always had the potential to become the leading theory of ageing18. Since then we have accumulated overwhelming evidence that a calorie-restricted diet helps flies, worms, rodents, monkeys, and even humans to live significantly longer19.
To eat in a calorie restricted way, we need to reduce our macronutrients (carbohydrates, fats and protein) by about one-third from what is recommended. This means that instead of eating the recommended 2000 kilocalories a day, humans should eat only 1200 kilocalories a day. Scientists have worked out that if a human cut their calorie intake by 30% from the age of thirty, they would add seven years to their life20. This is an astonishing result and, by way of comparison, is about the same that we would benefit by eliminating all forms of cancer plus all heart disease!
If we can do this then we will trigger a long list of significant health benefits:
Protection against oxidative damage
- Gerontogene activation — switch on the SIR gene and switch off the Daf-16 gene
- Lowering our core temperature (which has also been shown to extend life)
- Reducing insulin resistance — insulin is the hormone that clears glucose out of the bloodstream and stores it safely in fat cells. As we age, this becomes a more difficult process requiring more insulin to do the job. This is called ‘insulin resistance’ and is seen as a central contributor to multiple chronic illnesses. The good news is that calorie restriction has been shown to be a very effective way to reduce insulin resistance. That then means less cancer, obesity, heart attacks and diabetes and, therefore, a longer life21,22.
This is all very exciting except for one problem. Consuming only 1200kcal of food a day for life is not as easy as it sounds. To put this into perspective — the average consumption in China might have been 1439kcal/day in 1961, but by 2013 it had climbed up to 3108kcal/day. The average consumption in the USA is 3600kcal per day23. So today most people would have to take a whopping 2/3 of the food off their plate every day to enjoy these benefits — a big ask.
So despite having the best track record in helping longevity, calorie restriction is not a very popular option. Instead, there are a couple of alternatives that have shown similar benefits and have proved to be very popular:
- Intermittent fasting: typically, one may eat nothing from 8 pm until midday (a 16 hour fast) and then eat three healthy meals in the remaining 8 hours. Intermittent fasting reduces insulin resistance without having to restrict calories24. It also reduces inflammation, switches on healthy genes and extends lifespan25.
- High-intensity interval training (HIIT): this is typically a twenty minute period of mixed weight lifting and aerobic bursts with rest periods in between. For example, you could do weighted squats interspersed with burpees. This has been shown to reduce insulin resistance and switch on longevity genes26,27.
The wheel turns full circle
So, we have moved from the Victorian notion that we die because we wear ourselves out, to the realisation that inflammation damages us and that swallowing vitamins might guard against this. We have progressed further to understand that restricting our calories is the most beneficial thing we can do — which practically speaking means that we should all practice intermittent fasting and daily exercise. And the world is embracing this — The Fast Diet, otherwise known as the 5:2 diet (eat normally for 5 days and fast for 2 days of the week) has stormed into popularity since its launch in 2013.
And although there are still plenty of couch potatoes, there is a growing group of people who exercise heavily in pursuit of wellbeing and health. 30,000 people run the Boston marathon each year, 40,000 people complete the London marathon, and each year 35,000 people race 107km in the Cape Town Argus cycle tour. This healthy lifestyle will certainly allow many of us to live healthy lives deep into our 80s. However, is it possible to overdo all this activity? Is it possible that after a lifetime of excessive exercise that we may — with respect to August Weismann — wear ourselves out?
Wear and tear revisited
While all this activity was going on discovering new sexy theories of ageing, Weismann’s theory was quietly evolving. It got beyond the notion that we die because we wear down our teeth. In the early 1960s, two scientists discovered that skin cells (fibroblasts) would divide a finite number of times and then die — they named this the Hayflick phenomenon after one of the two researchers. The point is that most cells wear out eventually and die.
A couple of years later the concept of ‘stem cells’ started to come into scientific consciousness with the understanding that when cells have divided and died, the body replaces them with new cells28. However, what happens when the stem cells run out? The short answer is that in most organs, the organ fails. For example, as women age, their ovaries fail and they go through menopause. There has been much debate about hormone replacement over the years, but we now know that women who take some form of hormone replacement live healthier and longer than those who don’t29. The point is that once the wear-and-tear of life starts to break our organs down, there are useful things we can do to build them back up again.
As we age, our stem cells become less efficient at generating healthy new cells and, as a result, our skin starts to wrinkle, our bones begin to weaken, and our muscles lose their strength30. In addition to degenerating stem cell quality, some tissues can continue to make stem cells forever (sperm stem cells for example) while other tissues run critically short of cells and this proves to be problematic in later life. This wear-and-tear of stem cells is so important that it has been suggested that ‘a living organism is therefore as old as its stem cells31.’
Do we have evidence that we can run out of stem cells? For a long time this was an unanswered question, until 2017 when an excellent study showed that when stem cells wore out in the brain, the brain and the body quickly aged and died. The study was performed on mice and scientists looked at the hypothalamus, which is the central part of the brain that relays messages between the body and the brain. When the neural stem cells in this area ran out, the mice aged rapidly and died. When stem cells were added to the hypothalamus, the mice lived extended healthy lives32.
Many elderly people who die of natural causes are often relatively healthy and then suddenly degenerate and die. It is entirely possible that this acceleration towards death is driven by dwindling stem cells at the centre of the brain — once they wear out, we quickly fade away.
If there was ‘One ring to rule them all,’ then it would have to be the calorie restriction theory. However, as we have seen from above it is far from the only player in the game. If I think about my cupboard full of supplements in my quest for my healthiest life, I would do well to throw most of them away and follow these guidelines:
- A lifestyle of intermittent fasting and daily exercise to mimic calorie restriction and give me the biggest benefit for longevity
- Cut out sugar and add daily exercise to boost my longevity genes and my energy-producing mitochondria
- I should only use vitamin tablets to replace what is deficient in my diet. Swallowing daily high-dose vitamins could switch off my internal antioxidant systems and prove to be harmful. A good quality multivitamin three times a week is all that I need
- Although not a part of this article — sleep, stress management, and toxin removal are all important for my health and longevity. This is covered in my book ‘Younger for Longer.’
- Following this sort of lifestyle should get me healthily into my 80s. However, if I want vitality beyond this, then I need to consider the wear-and-tear theory and the fact that if I live healthily into my 90s, I may then start to run out of stem cells. Stem cell replacement is already happening and is a treatment that will be relevant in my lifetime. Just as importantly, I should look at how I can look after my cells better:
- Lowering my body temperature. Scientists have shown in flies, fish, and mice that reducing the core temperature of the animal, slows their metabolism, allowing cells to live longer and extends their life by a quarter33. Even in humans, a lower basal temperature and slower metabolism are associated with living longer34. I am hardly going to sleep in a bath of ice every night; however, I can be mindful not to run a marathon in 40 Celsius heat. This would heat my core and damage DNA and cells. Equally, I would do well to keep my home central heating at a cool 18 Celsius at night to allow for a comfortable temperature during the hours that I sleep
- Calorie restriction. Reducing my food intake to 1200kcal a day not only switches on healthy genes but also lowers my core temperature and slows my metabolism. Slowing the metabolism slows down cell turnover and contributes to longevity
- Meditation. Meditation slows the metabolism, extends telomere length (the ends of DNA which keeps cells healthier for longer) and encourages longevity. My life should not just be concerned with a constant stream of deadlines. Activities and sport need to be balanced with meditation and downtime
- Growth hormone (GH) has many roles, but an important one is how it stimulates stem cells in the body to divide into new cells35,36. In the 1980s, GH was seen as a wonder hormone allowing elderly men to revitalise and enjoy a youthful vigour37. However, it is entirely possible that this rejuvenation comes at the cost of burning up our stem cells. Scientists have discovered that people with high GH levels (an illness called gigantism) live much shorter lives than average. When these people’s GH levels are reduced, their life expectancy increases38. Other studies show that people with low GH levels have a better life expectancy than their peers39. If I were to consider taking growth hormone, it should be at very low doses indeed, to give benefit without burning through my stem cells.
There is no single ring to rule them all. Hopefully, when you are presented in the future with an amazing new pill that is guaranteed to help you live longer, you can approach it with a sceptical inquisitiveness armed with the knowledge of what theories of ageing it ought to benefit.
- Stadtman, E. R. ‘Review: Protein oxidation and aging.’ Science (1992): 257: 1220–4.
- Dreher, F. ‘Topical antioxidants protect against UVA & UVB sun damage.’ Curr Probl Dermatol (2001): 29: 157–64.
- Van Raamsdonk et al. Deletion of the mitochondrial superoxide dismutase SOD-2 extends life in Caenorhabditis Elegans.’ PLoS Genetics (2009). Accessed at: http://journals. plos.org/plosgenetics/article?id=10.1371/journal.pgen.1000361
- Alpha-tocopherol, beta-carotene cancer prevention study group. The effect of vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers. N Eng J of Med. 1994: 330: 1029-35.
- Eder K et al. An excess dietary vitamin E concentration does not influence Nrf2 signaling in the liver of rats fed either soybean oil or salmon oil. Nutr Metab (Lond); 2017: 14: 71
- Sayin VI et al. Antioxidnats accelerate lung cancer progression in mice. Sci Transl Med. 2014: 6: 221ra15.
- Hitomi, Y. et al. ‘Acute exercise increases expression of extracellular superoxide dismutase in skeletal muscle and the aorta.’ Redox Rep (2008): 13 (5): 213–16.
- Harman, D. ‘Free radical theory of aging: dietary implications.’ Am J Clin Nutr (1972): 839–43.
- Seo DY et al. Age-related changes in skeletal muscle mitochondria: the role of exercise. Integr Med Res: 2016: 5: 182-6.
- Zeigler DV et al. Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging. Aging Cell. 2015: 14: 1-7.
- Lanza IR et al. Mitochondrial function as a determinant of life span. Pflugers Arch. 2010: 459: 277-89.
- Mills K et al. Long term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 2016: 24: 795-806.
- Sinclair D et al. Impairment of an endothelial NAD-H2S signaling network is a reversible cause of vascular aging. Cell: 2018: 173: 74-89.
- Kenyon, C. et al. ‘A C elegans mutant that lives twice as long as wild type.’ Nature 366: 1993: 404–5.
- Sinclair, D. A. et al. ‘Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan.’ Nature (2003): 425:. 191–6
- Sinclair, D. et al. ‘Sirtuin activators mimic caloric restriction and delay ageing in meta- zoans.’ Nature (2004): 430: 686–9.
- Semba, R. D. et al. ‘Resveratrol levels and all-cause mortality in older community- dwelling adults.’ JAMA (2014): 174: 1077–84.
- McCay C.M. et al. ‘The effect of retarded growth upon the length of lifespan and upon the ultimate body size’. Nutrition. 1935: 5: 155–71.
- Lee C. et al. ‘Dietary restriction with and without calorie restriction for healthy aging.’ MC (2016): 5. Accessed at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755412/
- Speakman J.R. et al. ‘Starving for life: What animal studies can and cannot tell us about the use of Caloric Restriction to prolong human Lifespan.’ J Nutr 137: (2007): 1078–86
- Larson-Meyer, D. E. et al. ‘Effect of calorie restriction with or without exercise on insulin sensitivity, B-cell function, fat cell size and ectopic lipid in overweight subjects.’ Diabetes Care (2006): 29: 1337–44.
- Longo, V. D. et al. ‘Evolutionary medicine: from dwarf model systems to healthy centenarians?’ Science (2003): 299: 1343–6.
- Roser M et al. Food per person. Our World in Data. https://ourworldindata.org/food-per-person
- Anson, R. M. et al. ‘Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake.’ Proc Natl Acad Sci USA. 2003: 100: 6216–20.
- Martin, B. et al. ‘Caloric restriction and intermittent fasting: two potential diets for successful brain aging.’ Ageing Res Rev (2006): 5: 332–53.
- Keshel, T. E. et al. ‘Exercise training and insulin resistance: a current review.’ J Obes Weight Loss Ther (2015): 5: S5–003.
- Kohman, R. A. Et al. ‘Voluntary wheel-running reverses age-induced changes in hippocampal gene expression.’ PLOS One (2011): 6: e22654.
- Becker A J Et al. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature. 1963, 197: 452-454. https://tspace.library.utoronto.ca/retrieve/4602/nature_1963_197_452.pdf
- Sarrel, P. M. Et al. ‘The mortality toll of oestrogen avoidance: an analysis of excessive deaths among hysterectomized women aged 50 to 59 years.’ Am J Public Health (2013): 103: 1583–8.
- Ahmed ASI et al. Effect of aging on stem cells. World J Exp Med. 2017: 7: 1-10.
- Ho A D et al. Stem cells and ageing. EMBO Rep. 2005: 6: S35-38.
- Zhang Y. et al. ‘Hypothalamic stem cells control ageing speed partly through exosomal miRNAs.’ Nature. 2017: 548: 52–7.
- Keil, G. et al. ‘Being cool. How body temperature influences ageing and longevity.’ Biogerontology (2015): 16: 383–97.
- Simonsick, E. M. et al. ‘Basal body temperature as a biomarker of healthy aging.’ Age (2016): 38: 445–54.
- Kawa M P et al. Effects of growth hormone therapeutic supplementation on hematopoietic stem/progenitor cells in children with growth hormone deficiency: focus on proliferation and differentiation capabilities. Endocrine. 2015: 50: 162-175.
- Chen Y et al. Distinct effects of growth hormone and glutamine on activation of intestinal stem cells. JPEN. 2017: https://www.ncbi.nlm.nih.gov/pubmed/28510488
- Rudman, D. et al. ‘Effects of Human Growth Hormone in Men over 60 Years Old.’ N Engl J Med (1990): 323: 1–6.
- Orme, S. M. et al. ‘Mortality and Cancer Incidence in Acromegaly: A Retrospective Cohort Study.’ J Clin Endocrinol Metab (1998): 83: 2730–4.
- Milman, S. et al. ‘Low Insulin-Like Growth Factor 1 Level Predicts Survival in Humans with Exceptional Longevity.’ Aging Cell (12 March 2014). http://onlinelibrary.wiley.com/ doi/10.1111/acel.12213/full