Book Summary: Outlive

By Peter Attia & Bill Gifford

Outlive is the book by Peter Attia and Bill Gifford looking at how we can improve our healthspan - how long we live at a good quality of health. He is a physician for whom this is the focus of his clinical work. Indeed, it is interesting to hear the story of his professional journey with which he opens the book. He started his medical career as a cancer surgeon, operating on those with significant cancer and removing the tumours that were the centrepoint of the disease. However, he notes his increasing disillusionment with this. He gives the analogy of running around trying to catch falling eggs; no matter how hard he tried, they kept coming and there were many that fell through. Indeed, he was so dispirited that he left medicine for a time before coming to recognise that the problem is the lack of focus on prevention. He highlights how the current medical system (he terms it Medicine 2.0) is great at a number of things: treating infectious disease, dealing with trauma, undertaking operations. However, it has traditionally given relatively little focus on prevention, being reactive rather than proactive. The result is the incredible burden of cancer, cardiovascular disease, and neurodegenerative disease that we now see. To really improve our healthcare system we need to move our focus here, to Medicine 3.0.

Reimagining Medicine 

Modern medicine has been a huge success in many ways. Prior to this (Medicine 1.0) there was very little effort to determine the true causes of disease and effect of interventions. They were surrounded in mystery and ceremony and it is clear that many (e.g. blood letting) were actively harmful, as well as being mostly ineffective. Medicine 2.0 applied many of the lessons of the scientific method and delivered a system of evidence based medicine that led to huge improvements in health. As Attia notes, this was particularly effective at dealing with ‘fast’ causes of death: infections, trauma, surgical pathology. In contrast, ‘slow’ death was greatly neglected. The research was harder and the clinical targets were less clear. It is also likely that the financial incentives were less. As such, even when medicine did focus on prevention, it was often very late in the disease process. Secondary prevention (prevention of a disease getting worse) was more commonly the approach that aggressively preventing it developing at all; reactive rather than proactive.

As a result, the dreaded diseases of ancestors are gone, and we face the new horsemen:

• Metabolic disease/ diabetes 

• Cardiovascular disease 

• Cancer

• Neurodegenerative disease 

These are interconnected in multiple ways, and core features of our modern world. The key problem in regards to medicine is that they develop over a very long time (decades) and are deeply related to how we live our daily lives. As such, this is where Medicine 3.0 needs to look.

Alongside this is the impact of ageing. This is defined as the progressive loss of physiological integrity, and can be considered as physiological as well as purely chronological. The main domains are Cognitive, Physical, and Emotional. The goal is to stave off decline or even actually improve in these domains over time. That is, to effectively expand our healthspan. This is the duration of quality life we have, and is more relevant to most people than just lifespan. If we only focus on living longer, we can be left with a significant period at the end of our lives with poor health.

Medicine 3.0

Attia gives an outline of what a new version of medicine could look like. He highlights some features which need to be central:

1. Prevention is better than cure

2. Everyone is different 

3. Risk needs to be truly addressed

4. Incentives are usually poorly set

This will need active and engaged patients; indeed, individuals will likely need to take the lead in their own health. This is likely to be a challenge in some settings, and Attia notes that there will therefore need to be a clear focus on strategy, as opposed to just tactics, as is often the case currently. Moreover, the challenges posed by the timescales involved mean that the evidence base is necessarily different from that of Medicine 2.0. The randomised control trial, the gold standard of medical research, is very expensive to run, and even the very best can only really be conducted for a few years. As already noted, the scale here is decades. Attia therefore thinks of these ideas as evidence informed drawing from a number of less robust sources that, in cases of extensive convergence, can point to the truth. These sources include the case studies of centenarians, evidence from animal models, extrapolation from the research on major diseases, and Mendelian randomisation work.

The result is that Attia thinks there are 5 main domains where we can comment on what can help improve our health span. These are:

1. Exercise

2. Nutrition 

3. Sleep

4. Emotional wellbeing

5. Exogenous molecules 

Before he looks at these he analyses the components of “The Four Horsemen”. These represent to four key diseases of modernity that we really need to focus on. 

Metabolic Syndrome 

Metabolic syndrome refers to the widespread changes that have a strong association with calorie excess - in particular obesity and insulin resistance (and subsequently diabetes). The metabolism of calories is a bit more complex than many may think. Excess glucose becomes glycogen in muscles (75%) and liver until these are saturated. At this point it gets converted to triglycerides and stored in subcutaneous fat. This is okay and the normal storage spot for such excess energy. However, when ongoing calories excess continues beyond fat cell management, these spill over to be stored elsewhere. This excess fat storage is where many of the problems arise. Sites of storage include the abdominal cavity, liver and muscles. It seems that muscular storage is a major driver of insulin resistance and this is the first marker of deteriorating metabolic health. The pancreas will usually respond adequately to start with but then struggles with the ongoing demands. This is the subsequent trajectory that leads to diabetes and the other adverse features. Fatty liver is another major problem here - this is soon to be the biggest cause of liver transplant! It is associated with obesity, dyslipidemia, and diabetes and seems to represent the body struggling to store such large amounts of excess energy. The liver becomes so full of fat that it begins to scar and fail to function.

The primary driver of metabolic syndrome seems to be calorie excess. This is something that we are not well evolved for, having spent almost our entire history in an environment of calorie deficiency. A good example is fructose, the major sugar of fruit. The human body is quite poor at handling this in excess, seemingly because of a relative quirk of evolution. We lack uricase that breaks down urate, which is a major product of fructose as well as purine rich foods (urate excess is the cause of gout). Fructose is a major supplement in many modern foods such as pop drinks because of the positive consumption sensations we get. When in this format it rapidly overwhelms the gut processing and leads to peaks of insulin (Interestingly, we don't seem to see this effect when it ingested within the matrix of solid fruit).

Metabolic syndrome is closely linked with the other horsemen and so needs addressing first. Interestingly, activity is a useful protector because it helps mobilisation of sugars, improving their storage as much as it improves their expenditure. However, it is ultimately energy balance that is a key determiner in metabolic syndrome risk - if you consistently eat more than you expend, problems will start to arise. 

Cardiovascular Disease

The term cardiovascular disease here refers to the atherogenic disease process that occurs in the blood vessels of the body, particularly the coronary arteries which supply blood to the heart itself. This remains the biggest killer in the US and developed world, which is sometimes a surprise for people (cancer often emotes more fear). A shocking statistic is that in almost half of cases, the first presentation of cardiovascular disease is sudden death. That is, it can remain silent until it is very advanced. The pathological process is very well understood by clinicians and its current prevalence seems to be a result of processes that are particularly relevant in today's society. There is some genetic influence, but partly through how this influences the modifiable risk factors, such a lipid handling.

Lipids are heavily involved in the process. Cholesterol has a bad name in the popular imagination, but is not as bad as previously thought - most cholesterol is synthesised by the body and it is an essential part of all cells. Instead, it is the form of lipoprotein that is relevant and it is related to the mechanism of how fats are packaged. Lipoproteins are the body’s mechanism for transporting lipids around the body, as they are insoluble in the aqueous solution of the blood/plasma. As such, they get packaged in different molecules, of which the lipoproteins are key (essentially a protein coat for the lipids). Apoprotein B is the ‘bad’ form of protein in this regard, as opposed to type A, and this is widely found in low density lipoproteins (LDL) and very-LDL. These seem to be much more susceptible to deliver lipids to the sub endothelial space when they end up there. Hence, they are associated with atherosclerosis where lipid plaques build up within the walls of blood vessels. 

Inflammation also plays a role in atherosclerosis, probably through the effects on the endothelium and increasing permeability to these problematic lipoproteins. This can arise from well recognised risk factors such as smoking and hypertension (high blood pressure) to contribute to the risk of cardiovascular disease. The very positive point here is that we know this disease process very well and we have great tools to treat the causes. However, it is an exposure related risk and so the key to risk reduction is early detection and intervention. Dietary changes will be a component, but Attia believes that drugs are often needed to get the risk down to the lowest level in many people.

Cancer

Cancer is the next major disease and is perhaps the disease that concerns people the most. It is the biggest killer after cardiovascular disease. Cancer is essentially just the loss of growth control within our normal cells, particularly the loss of programmed death. When this is coupled with the ability to spread around the body (metastasis) it results in our own out of control cells causing widespread damage. Beyond this common description, cancer is actually an incredibly varied collection of diseases. There is a huge variation in their genetics and pathophysiology and whilst we do know quite a bit about risk factors, an awful amount of the risk is simply about luck. 

Attia notes that this therefore needs an aggressive approach to management through minimising risk factors, intensive screening and effective treatment. Several of the recognised modifiable risk factors overlap across the cancer types:  smoking, insulin resistance, obesity, and maybe pollution. Understanding the pathology can help us with this prevention. There are essentially two key characteristics that may enable us to tackle it better: Metabolic dysfunction and immune evasion. Cancer cells are very abnormal metabolically. They have a very high glucose demand and, as such, there seems to be a link to metabolic syndrome in their genesis. Obesity and hyperinsulinaemia and linked to cancer risk, as are other growth factors like ILGF and PI3F.  As such, they may also provide some mechanism for managing it. Fasting and ketogenic diets have some positive effects, even if they are not cures. It may be that they can augment therapy because of their negative effects on tumours whose metabolic states tolerate these systemic changes poorly. Regardless, it is also another reason to strongly avoid any insulin resistance. 

Immunotherapy is a highly promising area of treatment as this targets the second major component of cancer pathology - the evasion of our immune systems. The goal is to get the immune system back on track to identify cancer as abnormal rather than mistake it for self. There may be some preventative role here when it comes to thinking about immune system health but this is particularly a focus for promising treatments. As an example, CAR T therapy programmes the body’s own T cells for optimal attack against the cancer. 

However, all these treatment strategies need the cancer to have been detected. This is a major challenge given the occult nature of most forms. The clearest understanding that we do have about cancer is that early treatment is always better than late. Early means fewer cells which means fewer mutations and more responsive to treatment. It may also allow pre-cancerous lesion removal, such as bowel polyps. All this has lead to Attia to be a strong advocate for aggressive early screening. There is some controversy here, as all screening carries some risk, and it is interesting to see that many of the screening programmes that he himself practices are quite a bit more intensive that nationally advocated ones. 

Neurodegenerative Disease

This bracket includes Alzheimer's disease, but also parkinsonism and other forms of dementia. The mechanisms behind these disease are still being understood, but there do seem to be overlaps with some of the other disease processes just discussed, especially metabolic syndrome and cardiovascular disease. Whilst there has been the identification of beta amyloid and tau proteins in neural tissue, this current model of causality may be not fully correct. Attempts to treat it via such a mechanism have failed so far. An alternative explanation describes potential metabolic causes with reduced oxygen delivery and altered glucose handling. This seem potentially causal, or at least would fit well with some aspects of correlation, and the amyloid and tau would therefore be consequences rather than causes. This would suggest that vascular dementia is part of the same family rather than a different pathophysiological process.

Positives about this perspective mean that prevention seems feasible and perhaps even better than with cancer. Exercise currently has the strongest evidence for benefit, whilst other dietary factors are focused on improving cardiovascular and metabolic health as above (for example, a Mediterranean diet is advocated). There is perhaps some role for omega fatty acids, appropriate B vitamins and vitamin D, but the strength of recommendation here is less. Being ‘cognitively fit’ also seems to provide a buffer for decline, because of the inherent redundancy in the brain. 

Thinking Tactically

Having understood the nature of the problems, it is then time to turn to the best methods for dealing with them. Attia categorises these strategies into 5 domains:

• Exercise- aerobic efficiency, max output, strength, stability 

• Nutrition 

• Sleep

• Emotional health

• Exogenous molecules 

Exercise 

Exercise has the biggest positive impact on health. Indeed, when you look at the magnitude of some of the benefits it is almost unbelievable. However, the term exercise encompasses many different physiological meanings. These subdomains are best reviewed individually as all are important for overall health.

Cardiovascular fitness is probably the most important. This essentially refers to the ability and efficiency of the cardiorespiratory system to undertake its function; that is, the delivery of nutrients to tissues, and the removal of waste products. There are many steps along this physiological chain, from the lungs, through to the heart, the blood itself, and the tissue mitochondrial function (and this is far from a complete list). What seems to be a particularly valuable predictive factor of longevity is the VO2 max. This is the maximum amount of oxygen that the body can deliver. The measured VO2 max is strongly inversely correlated with all cause mortality and this effect covers the whole normal distribution. The difference in lifespan is in the order of years! 

Muscle strength is very similar. Muscle strength, alongside but more relevant than muscle mass, is highly correlated with lifespan and healthspan. The decline in strength with age is notable and associated with more health and functional problems. This is probably bidirectional - there is less strength for doing stuff so less is done. There is a clear age related decline in muscle mass and strength which is an inevitable part of ageing, but this can be influenced. The challenge is that it is harder to build back up the older we get, so we really need to build up to a strong starting point to be able to withstand the decline. 

Overall, Attia advocates a radical rethink of our physical health with regards to age. Yes, function does inevitably decline, but we can massively impact this by having a better baseline and continuing to resist the decline. He describes the Centenarian Decathlon - picture the activities that you want to be able to do and train for these, as an athlete would. This generally means being a generalist and achieving a very good baseline as early as you can so that the natural decline will still leave us with plenty of functionality. Importantly, we have to be targeted and dedicated in our effort here, as these are very unlikely to occur incidentally in the modern world.

His approach to the physical training has 4 main strands:

• Zone 2 training

• VO2 max optimisation

• Training of muscle strength

• Stability work 

Zone 2 training refers to a specific range of cardiorespiratory activity. This stage is moderate exertion and a state that should have a durable equilibrium i.e. you can undertake it for a long time. Physiologically it is often described as a heart rate of about 70-80% of maximum heart rate and stable lactate measurements in the normal range. However, it is often best considered practically as the activity you can undertake whilst still just about being able to complete sentences. You should be a bit breathless, but able to converse. Training in this zone has an aerobic focus, improving mitochondrial health and creating a foundational fitness for other physical activity and life overall. Attia notes that regular training to this purpose is needed, and he advocates about 80% of the time for physical exercise be directed here. 

As already described, the VO2 max represents the upper limit of what the cardiorespiratory system can achieve. It is a deeply unpleasant state and unsustainable for anything but a short amount of time. However, it is this value which has the incredible correlation with increased lifespan. Zone 2 training will benefit VO2 through its overall cardiorespiratory benefits, but a greater degree of physiological stress is also needed to ‘train’ your VO2 max. This is in the form of some high intensity aerobic activity, such as with high intensity interval training. The interval nature is needed because of how unsustainable it is, and the challenge for some is that the activity is generally quite unpleasant to endure. However, Attia advocates that it is only really needed in relatively lower volumes than zone 2 training, perhaps just once a week. 

Strength training needs to be through dedicated resistance training. This has a functional component but is also protective. As noted, there is a rapid decline in muscle strength and size with ageing which requires the generation of a surplus in our younger years to allow deterioration. The specific activity will vary depending on age and goals, but Attia likes to focus on functionality, such as actions of pull, hip hinge and grip strength.

Finally, stability is an often neglected part of physical health. Attia often starts with this as part of physical management. The major role is in minimising injury which can be devastating in the older population. It is essentially about optimisation of movement, perhaps a sense of retraining what we did as growing children when we were still exploring our bodies. Eccentric strength (controlled relaxation) is as important as concentric strength (controlled contraction) which comes together to result in neuromuscular control. There are many components that Attia describes, but a reconsideration of breathing is a central starting point. This is often done poorly without an appropriate coordination to pressurise the abdomen and connect the upper and lower body when needed. 

Diet and Nutrition 

This is an area where it is very challenging to get scientific answers. There are a lot of strong opinions and poor science that has led to the wide range of diets and advice on offer. The problem is that we are almost completely unable to experiment and so are very reliant on epidemiology. As such, unlike with exercise recommendations, there is simply less confidence around what can be stated. However, some things seem likely: don't overeat; get enough protein and key nutrients; vegetables are good food; we are omnivorous and this diet seems okay. The best research has supported the so-called Mediterranean diet which seemed to be beneficial for CVS health. 

When considering what we eat, how much we eat is an important factor. Some ways we can think about this include:

• Caloric restriction - restricting how much we eat

• Dietary restriction - restrictions on certain food groups

• Time restriction - restricting when we eat

Calorie restriction seems to have the strongest evidence of benefit. If you eat less than you need you lose weight. Over consuming calories is a component of metabolic disease. And there is some limited (animal) research about longevity benefits. However, the big challenges are measurement and hunger. Modern apps have helped, but it can still be difficult and inaccurate to count calories. More relevantly, calorie restriction can be done less skillfully so that you feel much hungrier. In contrast, some diets can give lower calories and feel less hunger-provoking because of the inclusion of foods that are simply more satiating.

Dietary restriction can be a bit harder as there is such variability in options (vegetarian, vegan, dairy free, ketogenic, etc). Attia was previously a strong advocate of the ketogenic diet, with major carb restriction and the subsequent switch of metabolism to using ketones as the major energy fuel. He now notes that this isn't for everyone, although there remain many advocates. Overall, a lot of this comes down to watching your macronutrients:

• Carbohydrates 

• Protein

• Fats

• (Alcohol)

Carbohydrates are a major focus of many diets given the fact that it is often through excess carbs that many modern diets achieve their calorie excess. This seems a very reasonable approach. Attia was previously a major fan of the keto diet which essentially removes almost all carbs and switches you to a fat base. This is not for everyone, as he now appreciates. However, controlling the total volume of carbohydrates is important for any diet. Another key goal is to optimise any carbs that you do get, the goal being to reduce blood glucose spikes and the corresponding insulin spikes. As a rough rule of thumb, the less processed and more complex, the better. Consuming them as plant based is very helpful as the slower peak of release improves the insulin profile. Similarly, eating alongside other macronutrients can also help optimise the absorption and hunger profiles. Snacking on highly processed, simple carbs is the antithesis of this. As part of this analysis, continuous glucose monitoring is something that he advocates. This can help the patient understand how their diet results in glucose responses, which will vary amongst individuals. 

The answers around protein seem more straightforward.  You need a good amount of protein to maintain your lean muscle mass and this is more that the bare minimum that often gets quoted in guidelines (0.8g/kg/day). Attia thinks it needs to be much more - at least 1.6g/kg and in some cases over 2. High exercise intensity will need more for muscle upkeep. The best source of this seems to clearly be animal sources. Plant sources are less bioavailable and the breadth of the amino acids is narrower. It is still possible but needs much more thought. In general it is best to space out the consumption, probably across 4 meals through the day.

Fats are often even more controversial and complex. They have been much maligned but are an essential part of a healthy diet. Much of the upset comes from their calorie density (over double that in carbs and protein), but also the recognition of their effects on lipid profile and the subsequent cardiovascular disease risk. The research is complex. Monounsaturated fats seem best, then polyunsaturated then saturated (the saturation profile refers to how many hydrogen ions could be added to the lipid chain). Again, plant oils are better (especially olive oil) and then nuts and animals. Omega 3 and 6 and fish oils seem to be also valuable, thus including oily fish in diets is a common recommendation. They may need to be supplemented unless a decent amount of oily fish is consumed (it is often not). 

Alcohol is an interesting addition as a macronutrient but Attia notes that it often forms a notable part of people’s diets. It is a major source of calories and little else. It seems that there is no good amount of alcohol. Any positive effects observed in studies all seem to be confounded by the healthy user bias - healthy users are the ones who can drink moderately. In contrast, there are clear deleterious effects of the calories, changes to lipid handling, and sleep disturbance. Attia himself still drinks moderately, accepting some of the adverse health effects whilst valuing the enjoyment he gets from it, as well as the social component. It has made him much more careful with the quality of any alcohol he consumes (it has to be worth it - no cheap wine!) and he mitigates as many negative factors as he can (such as ensuring there is a suitable gap before sleep). 

Time restrictive eating essentially means some form of fasting. There are multiple different strategies here but it essentially acts as a different form of calorie restriction. Attia thinks of this as a fairly extreme response to difficult metabolic cases as most fasting is too short to cause major benefits and there is a clear cost. The cost is the reduced protein intake and subjectively reduced energy that reduces activity. This therefore seems self-defeating given the primacy of exercise for health benefits. The evidence base behind it is also not persuasive, hence the reservation of it for extreme cases. 

Sleep 

The importance of sleep is increasingly being recognised. It affects all aspects of health; physical and cognitive. Our physical health is actually quite badly affected by poor sleep. This seems to be stress mediated. Our metabolic health becomes very deranged, with detectable insulin resistance from just short term sleep upset. Other adverse effects include increased appetite, blood pressure and heart rate. Disturbingly, there is a close relationship with cognitive decline. The actual direction of this relationship isn’t clear but it seems plausible that poor sleep contributes to the pathology of neurodegenerative disorders.

His tips for better sleep include:

• Very dark room

• No alcohol 

• Calm time before bed - avoid stressors, minimise blue light 

• Exercise in day

• Daylight in day

• Fixed times of sleep

• Avoid naps

In general, drugs have no role in improving sleep. Trazodone is one he notes may have a relatively favourable profile, but is definitely not to be considered as routine. Day time caffeine can cause problems for people but there can be a notable degree of variation in how people deal with it. Some of this may be genetic so a good rule is to limit it and to have earlier in day

Emotional Health

Whilst left until the end, emotional health may actually be one of the most important factors in healthspan, yet often neglected because of its complexity. As well put, why would you want to live longer if you are miserable? A eudaemonic life is the ultimate goal, and physical health is as much a mechanism to achieve this as anything else. Attia himself is very candid about some of the major challenges he faced with his emotional health. There are multiple components but trauma can be a contributor to problems. This is more an area for therapy than medicine, but this needs open consideration. 

More philosophically, it can be a useful reminder to look at the distinction between resume virtues and eulogy virtues. It is the latter that can be forgotten about when our lives get busy, but it is these that we often truly wish for. Reflection on our goals and trajectory in this context can help. In addition, mindfulness has great value here, as it allows an awareness of how much your own thinking contributes to negative feelings. A really good point that Attia makes is how it can still be difficult to think yourself out of negative emotions, a real limitation of cognitive behaviour therapy and similar approaches. Instead, just doing something can be very helpful. This is basically enacting the right things, even if the mood isn't right, and the positive effects then arise from the behaviour, rather than the cognitions. Making sure you do exercise and eat and sleep well are good examples of this and indicate some of the potential virtuous (and vicious) circles that can be attained. 

Exogenous Molecules

This essentially refers to drugs and more traditional therapies. They still have a major potential role but only within some specific domains and with greater costs (mostly economic, but sometimes risk). As already discussed, Attia notes that the anti-lipid drugs we have are incredibly effective, to the point where they seem to be better than some of the best results that can be achieved with diet and exercise. Similarly, much of the treatment of cancer will remain under the umbrella of Medicine 2.0, even if a lot of the prevention is not. The brevity of this section is perhaps a good example as to how much of a challenge pharmacological prevention has been in comparison with treatment.

As a more academic interest, there is continuing research about pharmacological approaches to affect the very ageing process itself. These sound a long way from clinical practice, but the history behind molecules like rapamycin is fascinating.

Summary

Attia is looking to push the next boundaries of improved healthspan, but the current medical model seems to be struggling with this. Instead, a much greater emphasis on prevention needs to be take. This is essentially a lifelong endeavour. There are 5 key pillars involved:

• Exercise

• Diet and nutrition

• Sleep

• Emotional health

• Exogenous molecules

Perhaps the most exciting thing about this book was the magnitude of effect of some relatively achievable goals. You don’t need to become a marathon runner, but improving your cardiovascular fitness by even modest amounts will notably improve your health. Of course, just because something is simple doesn’t mean that it is easy. Methods for effectively implementing such lessons in the real world will no doubt be the hurdle for many, but the potential effects are empowering to see.