Ageing (Part II): not without a fight

Welcome back to our exploration of ageing and strength.

To recap, in part I of this article (here if you haven’t read it) we conceptually mapped out the ageing landscape as follows:

  1. Ageing is a multifactorial, complex process involving virtually all biological pathways
  2. For each individual, there likely exists an ideal ‘healthy’ ageing trajectory and multiple variations of this, depending a lot on pathology/disease burden
  3. Compression of morbidity: that although we cannot feasibly extend our limit lifespan, we can extend our health span
  4. Four proposed horsemen of the ‘geriatric apocalypse’; metabolic syndrome, sarcopenia, osteopenia, and frailty.
  5. A hint toward our own internal ability to reliably resist these horsemen, covered more in depth in this second part

Part I looked at the state of play with the ageing landscape.

This article, part II, will look at the mechanisms we can leverage in our favour in the battle against entropy and decrepitude.


WHAT WE ARE FIGHTING AGAINST; DEFINE THE ENEMY

As previously discussed, deaths due to infection, malnutrition or violence have been largely replaced by chronic disease; diabetes, ischaemic heart disease, stroke, dementia, cancers, frailty syndrome and so on [1]. The aforementioned ‘old world’ foes had clear cause and effect; smallpox, TB, or measles would flatten the healthiest person, starvation decimated millions (China’s Great Leap Forward, as an example, often slips under the Western educational radar), and intentional trauma or occupational hazards were much more frequent (not withstanding the current knife crime trends across parts of the UK) [2]. Sanitation, vaccinations, occupational safety, and antibiotics have already given us the bulk of our gains in life-expectancy over the millennia.

As we can see, modern threats are less dramatic, although no less lethal, than those some hundred years ago.

share-of-deaths-by-cause-2016.png

CHRONIC DISEASE AS THE STEALTHY ASSASSIN

We do a lot of things to stop bad stuff happening: drinking fluid so we don’t die, washing our bods so we don’t stink up the office, paying tax so the man doesn’t get you, taking the dog out so it won’t crap on the floor.

However, dying, stinking, going to jail, and dealing with crap are, relatively speaking, very immediate-term things that need your attention. Chronic disease, however, is a stealthy assassin, characterised by a lethal paradox; it is by far and away the biggest cause of mortality, but also the least likely to cause any alarm or notice, until a threshold event such as a myocardial infarction, stroke, or formal diagnosis is made.

We are hardwired with quirks or ‘biases’ that filter the onslaught of infinite information we confront each day, and abstracted threats such global warming or chronic disease collide with the many walls of optimism bias, cognitive dissonance, discounting bias, and sensory bias, to name but a few. In day-to-day, low threat states, we tend to view information asymmetrically, ‘incorporating good news into [our] existing beliefs while relatively disregarding bad news’. [3]

The machinery of the brain does not fully react to something until we detect it in the flesh [4]

The decision to change can be highly personal and idiosyncratic to the individual, with mind-blowing transformations scattered throughout the internet (Arthur Boorman, the ex-paratrooper, epitomises this). Although the challenge of behaviour change in response to a distant threat remains a critically important problem, it also remains the focus of an article separate to this one.

 

ENTROPY AND ADAPTATION

The law of entropy: After we reach adulthood, our biology inevitably tilts toward a downward trajectory: DNA unravels, oxidative damage accrues, brain tissue atrophies, cardiac function declines, and nature invariably takes its course. This is the way of the life and death cycle. Despite this inescapable truth, another golden law of nature remains latent, one that all biological organisms are shaped by: adaptation. This law can be leveraged against the grasping claws of painful entropy, as typified by disease and decrepitude, and serve as a best bet in striving to be all that we can be, right up to the end. To remain still is to go backward/downward, and maintenance, let alone improvement requires forthright effort.

Adaptation is realised by undertaking a bout of stress (loading the organism), followed by recovery and subsequent compensation by the body to a new, higher baseline. Theoretically, if we continue to increase a stressor over a period of time, the body will continue to adapt to higher and higher new baselines. This illustrates a principle that is the engine of continued adaptation and improvement: progressive overload. Although an over-used and over-simplified example, Milo’s increasing strength carrying the growing calf each day epitomises this, so too can we leverage growing stressors on the body to compensate and adapt furthermore, in a compounding manner.

Screen Shot 2019-07-10 at 23.31.07.jpg

“The fundamental phenomenon of all organic life is change of form (or movement), sometimes so slight as even to evade the microscope.” – Eugene Sandow

Physical movement can fulfil the criteria to ensure the adaptation effect required to pull up on the centre stick of our health span trajectory. But to limit this article, and maximise the compensation and adaptation effect, we need to consider what are the best means of progressively overloading the system. To this effect I will be concentrating on strength.


 

STRENGTH

Strength determines our ability to physically engage with and assert our influence in the world. It is a quality that underpins a wide range of specific and general physical skills and abilities [5], and it is also a variable that we can reliably and directly manipulate, unlike our genetics or IQ. Balance relies on the ability to sustain muscular tension with proprioceptive input; endurance relies on the repeated force output of a muscle over time; flexibility depends on the strength integrity of a joint and tissues to maintain positions at their weakest points. Although not the be all and end all, strength determines the energy that can be expressed across all these different domains, without which, nothing is possible. To use a blunt but effective quote;

“Strong People are harder to kill, and more useful in General” – Mark Rippetoe


 

STRENGTH AS A PRESCRIPTION

Strength training is the undertaking of a structured, progressive, repeated activity that focuses on overcoming resistance (such as barbells, your own body, stones, dumbbells etc) in order to build muscle and strength. Barbell training has often been positioned as the most optimal form of training in this regard as it fulfils some useful criteria: highly titratable (you can manipulate fractions of a kilogram), allowing the highest loads to be used and greatest degree of muscular involvement (and therefore greatest systemic effects), and being highly standardised and teachable (safety is crucial), amongst other benefits. It’s true that there is no other form of training that can load the lower body anywhere close to what a barbell squat can achieve. Saying that, as long as the strength training is repeatable, progressively overloaded, and safe, then hoo-rah.

As a medic, its interesting to think of strength training in two ways: as a medicine and for performance. The latter application is more obvious, but if we see this as a dose-able, prescribe-able medicine, then strength training possesses some unique properties when matched against pharmacological alternatives.

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THE POTENCY OF STRENGTH ON AGEING AND DEATH

Let’s first pan out to the macroscopic, birds-eye view. Large-scale studies involving more than a million individuals over a quarter of a century have shown that increased strength is associated with a 25-30% decrease in all-cause mortality, even independent of BMI or blood pressure [6]. Studies of literally millions of people have also repeatedly highlighted the close association between grip strength and deaths from all causes, with lower levels of strength correlating significantly with premature death [7,8,9].

Zooming into the level of the elderly individual (something we will hopefully all become), there are a reliably predictable number of ailments and traps that we may run into, and though some of these are unavoidable (bad luck, (epi)genetics, Zeus), many more are mitigable.

First, a reality-check.

Strength training, exercise, or any other lifestyle modification is not a panacea or cure-all. The fittest individual remains susceptible to the plethora of disease and, eventually, death. Cancer can be indiscriminate. Genetic diseases may cut you down regardless. Some will simply be too frail or debilitated to move. But arguably, there remain few pathways that have a greater bang for buck and allow us to hedge our bets so well.

So the suboptimal ageing adult is typified by fat in all the wrong places, insulin resistance, high blood pressure, weak and failing muscles, ’thin’ bones, fatigue, slowness, memory impairment, increased dependance, and a propensity to be taken out by illness or injury.

As opposed to the addition of strength, collection of each of the above very much makes you easier to kill. It also guarantees a great deal more misery in your days alive than may be otherwise necessary. It’s important to bear in mind that, although difficult to not fragment into a system by system approach when writing about this, that strength training exerts a synergistic, global effect across the entire body.

For the sake of a bit more detail, however, let’s dive into it:


HARDWARE UPGRADE; Muscle, bone and steel

First of all, strength training is a form of architectural building work. After around 30 years of age, muscle mass will naturally decline by 3-8% each decade [10], potentially paving the way to sarcopenia and frailty. Strength training can actually reverse this, and we can add more muscle tissue. A meta-analysis of 80 cohorts (>1300 individuals) found that just 20 weeks of training in men and women lead to an increase in 1kg of muscle mass, versus the natural loss of 0.2kg per year that would otherwise occur after age 50 [11]. Muscle tissue can be seen as a kind of savings account. It is accumulated through habitual saving (training), compounding over time and providing greater (health) security and (physical) freedom. Quality muscle tissue is attained through effort and over time, but augments our lives by providing a vehicle (our body) that we can rely on, help others with, and enjoy inhabiting.

Bone mineral density (BMD) loss similarly begins to occur slightly later in life, with a 1-3% reduction in BMD each year [10,12], skewing risk toward fragility fractures and increased dependance. Post-menopausal women are at greater risk still, when bone mineral density starts to drop off a cliff due to a drastic reduction in the hormone oestrogen. A Cochrane review [13] looking at post-menopausal women concluded that there is a small but statistically significant increase in bone mineral density of the spine and neck of femur resulting from exercise interventions. It’s likely that this grossly under-estimates the real effect, however. Looking at the 37 studies included in the review, only nine of these were actually using progressive resistance training. Others included tai chi, jogging, low-load strength training, dancing, and other exercise forms with much less potency for BMD increase than proper loading. Dr Austin Baraki, a powerlifter and physician, has cited this problem of ‘under-dosing’ in respect to studies looking at strength training or other exercise interventions, leading to a dilution effect in the results shown versus the actual potential benefits if adequately dosed (i.e. if they just put mo’ damn weight on the bar).

A threshold of loading must be reached for bone density to increase; “the mechanical load applied to bones should exceed that encountered during daily activities” [14], which means that walking, cycling, swimming, dancing, jogging are all sub-optimal as far as we are concerned for the battle of ageing.

Resistance training promotes the strength development of connective tissues such as ligaments and tendons, and also results in significant attenuation or reduction in levels of body fat, which is discussed further below.


 

RE-TUNING THE ENGINE; cardio-metabolic effects of strength on ageing

Study of cardiometabolic effects of resistance training has generally played second fiddle in the research, with primary outcomes usually focusing on metrics like muscle strength and size. Nevertheless, a recent systematic review [15] examining 173 randomised controlled trials concluded that resistance training did improve major cardiovascular risk factors. It turns out that strength training reduces levels of LDL cholesterol, triglycerides, fasting blood glucose, and CRP (an inflammatory marker) – all of which are major biomarkers used to assess cardiovascular risk. Additionally, reductions in systolic and diastolic blood pressure were comparable to aerobic training, with better endothelial function (the health of blood vessel walls), and improved compliance and reduced stiffness for blood flow. Its worth mentioning that almost all studies used machine weights, with only 10 of the 173 selecting free weights as the intervention for their subjects. Maybe the greater loading and systemic effects of free weight training would have resulted in even more favourable effects on these outcomes?

Metabolic Syndrome

Estimates assert that aro und a quater of the world population are affected by metabolic syndrome [16], characterised by high blood pressure, insulin resistance, dyslipidaemia, and visceral/truncal obesity. Exercise has been highlighted as being at least as effective as medication treatment in the secondary prevention of heart disease and pre-diabetes [17], and strength work can be a potent therapy in this regard.

You’ve probably heard that muscle is a highly metabolically active tissue. Muscle requires energy (ATP) for its ongoing survival and function. We derive most of this energy from carbohydrate, in the form of glycogen. Recall that carbohydrate ingestion stimulates insulin, which in turn clears carbohydrate out of the bloodstream into the cells. Insulin also stimulates fat production (because not all the glucose can be immediately used by cells or stored as glycogen).

Excess carbohydrate —> excess insulin —> excess energy that cells can’t utilise –> excess fat production —> eventual overwhelm of the system —> carbohydrate intake exceeds insulin response —> blood sugar levels rise —> diabetes manifests.

Muscle tissue is the primary and most effective glucose disposal system we have in the body. Two ways that we get rid of glucose:

  1. Insulin stimulates glucose transporters (GLUT-4) to make their way to the cell surface and shuttle glucose from blood into cell.
  2. Muscle contraction also stimulates increased translocation of GLUT-4 transporters, independent of insulin (via AMPK-dependant pathways).

Muscle contraction, at a certain threshold, acts like insulin, without any increase in the actual hormone.

More muscle tissue and muscle activity = more disposal and utilisation of glucose = less insulin required = less fat production and less insulin resistance [18,19]

When our muscles are atrophied and dormant, glucose pours into the body but has nowhere to be disposed, so is converted into more and more fat, snowballing the metabolic syndrome effect.

It’s notable that inclusion of some form of aerobic conditioning training is suggested in order to guarantee the biggest yield of cardiometabolic benefits, versus resistance training alone [20].


 

INFLAMMATORY LANDSCAPING

Recall that total body fat correlates with circulating levels of pro-inflammatory markers such as IL-6, TNF-a, CRP, and leptin, and that these in turn are implicated in atherosclerosis, neurodegeneration, tumour growth, and insulin resistance [21]. At the risk of over-simplifying complex biology, think of strength training and being sedentary as two control dials that we can actively manipulate. Strength training leads to decreased levels of fat and increased levels of muscle work and tissue. Being sedentary and doing no training leads to increased levels of fat and decreased levels of muscle work and tissue.

  1. Increased fat = increased pro-inflammatory factors throughout the body
  2. Increased muscle work and muscle tissue = increased anti-inflammatory factors throughout the body

After an acute bout of strength training, the body is in a catabolic state with raised levels of cortisol, adrenaline and inflammatory markers [22]. However, across the long term, repeated bouts lead to a global reduction in pro-inflammatory markers and an increase in anti-inflammatory markers [15,23]. We know that adipose tissue increases levels of pro-inflammatory IL-6 throughout the body. Strangely enough, Il-6 is also increased by strength work, but this ‘muscle contraction-induced’ form of IL-6 occurs in the absence of other pro-inflammatory markers, and actually has the reverse effect by way of reducing inflammation [22]. So, when we contract our muscles under load, we are squeezing out these anti-inflammatory myokines and concurrently reducing the nasties released by adipose tissue. Additionally, through hypertrophy over time, we increase the total level of muscle tissue, which facilitates greater myokine release, decreased levels of adipose tissue, and subsequently less pro-inflammatory marker release; we tip the balance of our inflammatory landscape more in our favour.


 

SOFTWARE UPGRADE; effects on cognition and neurology

Let’s say that what we have discussed above describes interventions to improve our ‘vehicle’; how about the ‘driver’? Attention, memory, planning, mood, quality of life, and global cognitive abilities. The effects of resistance training and exercise on brain and mental is trickier to measure, with a very variable and messy literature to wade through. Let’s strap our boots on.

DEMENTIA:

We begin with the identity thief that increasingly plagues our ageing population: dementia. Global prevalence in the over 60’s is around 5-8%, with more than 150 million projected to suffer this disease by 2050 [24]. Overall, the literature is mixed on the topic of dementia and exercise, and two very large scale studies have shown absolutely zero correlation between exercise and rates/severity of dementia [25,26]. Published in the BMJ, the DAPA trial, a randomised control trial examining aerobic and strength training in almost 494 individuals with mild-to-moderate dementia, found absolutely no effect on cognitive decline, with a trend even toward worsening cognition in the intervention group. Similarly, the Whitehall II study, following more than 10,000 British civil service employees, found no neuroprotective effects of exercise over a 28 year period. However, many reviews of other longitudinal studies do show a positive effect of exercise on reducing risk of dementia [27,28] although it must be remembered that the physical activity in these studies is self-reported, potentially muddying the waters of the evidence. Generally, though, it does appear that although reviews of longitudinal/prospective studies show moderate evidence of positive effects of exercise on prevention of dementia, reviews of interventional studies (such as RCTs) often show little or no evidence at all.

So what’s the verdict? Tentatively, I would say that there is low-to-moderate evidence that physical training can prevent or attenuate dementia onset, but the literature is varied.

COGNITIVE IMPAIRMENT AND NORMAL HEALTHY ADULTS

Moving on then, what does this minefield of research say about brain and cognitive health in those of us without dementia? Let’s get a bit of a primer on cognitive domains first of all by referring to our rudimentary diagram below:

Lobes_of_the_brain_NL.png

You probably already know that our brains are made up of regions that specialise in different functions. You can take your index finger and point to the back of your head, where a huge amount of brain real estate is dedicated to vision, or (if you are right-handed) to the left temporal part of your head, which controls production of speech. Although there are more domains, the literature commonly explores the following dominant themes:

  1. Executive function: planning, organising, self-control, rationalising etc. This is around the front of your brain (frontal and pre-frontal cortex)
  2. Processing speed and attention: pre-frontal and parietal cortex for attention, multi-regional for processing speed
  3. Memory: hippocampus primarily (also other regions)
  4. Global cognition: the overall cognitive ability, ‘whole-brain ability’

Cognitive impairment (CI) represents a degrading of at least some of the above domains, and is regarded by us medics as a pre-cursor and risk factor for developing dementia, which can be measured by tools such as MMSE (score of below 24/30 is a red flag).

Resistance/strength training appears to do well as a prevention/therapy for CI, with studies indicating that, for both healthy older adults and those with mild cognitive impairment (MCI), getting stronger is well correlated with improvements in cognition domains [29,30]. Although issues of measurement tools and standards may bias the consensus, the literature definitely indicates that executive function, attention, and global cognition respond well to strength [31,32], with less evidence for memory [33,34], although some authors do demonstrate improvements when averaging across the whole spectrum of cognitive ability [30]. A review of 25 RCTs also showed that strength work can significantly improve reasoning ability [28].

Due to lack of studies, no one really wants to commit to specific dose-response curves for training and cognitive function, but those who do dip their toe comment that longer periods (at least 52 weeks), greater frequency (3 versus 2 times per week) and higher intensities (such as greater tonnage lifted) yield the greatest benefits in cognition [33,34]. Others actually state that there is currently no demonstrable relationship between variables (intensity, frequency, duration) of training and cognition [31], but I’d go out on a limb and say that this is likely due to heterogeneity in the research, and that common sense and intuition would tell me ‘more gainz, more brainz’.

‘What are the mechanisms for all this?’, you yell at me.

Put simply, we think these benefits accrue from increasing actual brain tissue and improving cerebral blood flow. More specifically, neurotrophic factors like brain derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF) and insulin-like growth factor (IGF-1) increase in response to anabolic stimuli such as strength work, and contribute to increased cerebral blood flow, neural network maintenance and neurogenesis (growth of new brain and nerve tissue) [35,36,37]. Larger frontal cortex and hippocampus volumes (memory storage and pattern discernment area of the brain) have been radiologically demonstrated in trained versus untrained subjects. Regular exercise has been shown to increase hippocampal volume by up to 2% in ageing adults, versus the expected age-related loss of volume [35]. Epigenetic effects of exercise have also been demonstrated in animal studies [36], showing that increased motor activity affects mechanisms such as DNA methylation, histone modification and miRNA expression, which regulate the expression of genes involved in neuroplasticity and memory consolidation, for instance.


So there we have it.

My attempt to provide an overview of how strength training and exercise can be leveraged against our inevitable decline and entropy gives a pretty optimistic conclusion:

That we can have significant influence over our trajectory.

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