Posted on 5 May 2022
As we age, the way our bodies process and store lipids undergoes some changes, and you probably won’t be surprised to hear that none of them are good. There’s also increasing evidence that a reverse relationship exists between adipose tissue and ageing: by staving off weight gain, you might also be able to slow down certain aspects of the ageing process, allowing you live in good health for longer. Not all is lost, as while staying lean in old age is harder than when you are younger, weight gain isn’t inevitable. In this article, we’ll review the changes that occur with ageing that relate to lipids and their storage, and how excess adipose tissue might in turn promote ageing.
It won’t come as a surprise to learn that, on average, the amount of adipose tissue increases as people get older. Body Mass Index (BMI), calculated by dividing one’s body weight (kilograms) by the square of one’s height (metres), tends to increase until later life when it may decrease somewhat. The graph below shows the proportion of different age groups that fall into each BMI category in Sweden as of 2020.
As mentioned in part 2, the expansion of adipose tissue during adulthood is thought to be mainly the result of lipids being transported into existing adipocytes (fat cells), causing them to grow in size. But why does this happen more with advancing age? Scientists can’t fully answer that question yet, but there are a number of probable explanations.
The first explanation is also the most straightforward: older adults may simply exercise less and/or eat more than when they were younger. Even if someone continues to consume the same diet throughout their life, physical activity usually declines. This may happen at first because of time constraints related to work or childcare, and subsequently due to poor health in old age. Thus, as we get older, we have more excess calories that need to be stored as lipids, and our adipose tissue grows.
The second explanation is that older adults have a lower resting metabolic rate – that is to say, the rate at which the body consumes calories when not engaging in physical activity is lower in older age. The age-related loss of muscle mass (sarcopenia) is an important factor here, since muscle tissue consumes a large amount of energy even when it isn’t being used. There’s some uncertainty as to when this metabolic slowdown begins, though. Some research suggests that resting metabolic rate remains mostly stable until age 60, which would suggest that the first explanation is the main cause of weight gain in middle age. A slower resting metabolic rate would partly explain why it becomes harder to maintain a normal weight with age – you’re using fewer calories at rest than a younger person, and so it takes more effort to reach the calorie deficit necessary for weight loss.
We discussed in part three the differences between subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) and why the latter is generally considered to be ‘bad’. With increasing age, lipids tend to be redistributed away from SAT in favour of VAT. More lipids also get stored outside the adipose tissue, such as within liver and muscle cells, which is a bad thing because this promotes insulin resistance (again, see part 3 for a recap.) The loss of SAT is not only deleterious for the body’s handling of nutrients, but is also an important factor in skin ageing, making the skin thinner and contributing to the formation of wrinkles. Additionally, the amount of brown adipose tissue (responsible for generating heat) and beige adipose tissue (a type of tissue somewhere between white and brown) decreases during ageing.
Why these changes happen isn’t fully understood. Simple calorie surplus and weight gain during ageing explain part of the growth of VAT, since this tissue expands only after SAT is ‘full’. Changes in molecular signalling with age (such as hormonal changes and increased inflammation) are likely to play a role in the reduction of SAT in favour of VAT. Perhaps the most obvious example of this is that women tend to gain visceral fat following the menopause. Adipocyte stem cells – the cells responsible for generating new adipocytes – also die off during ageing. This makes adipose tissue less able to adapt and accommodate more lipids by forming new adipocytes, which could lead to excess lipids being stored in other tissues like liver and muscle.
Until this point, we have talked about adipocytes as fitting firmly into one category or another: white or brown, subcutaneous or visceral. However, adipocytes have some flexibility in their function. For example, during fasting or starvation, subcutaneous adipocytes start to behave more like visceral adipocytes and become temporarily ‘less brown’. This means they will release their lipid stores more readily than they would in a fed state, while restricting their own consumption of fatty acids when generating heat. This is a good thing: it means that adipose tissue can adapt to the needs of the body, soaking up excess calories in times of surplus, and releasing them when necessary.
This flexibility seems to decline with age: the adipocytes of older individuals don’t seem to adapt as well to the body’s changing demands for storing or releasing lipids. When an older person consumes a surplus of calories, their adipocytes are less able to shut down the release of lipids and to accommodate the new influx of nutrients. This may be caused in part by changes in adipocyte signalling (see below), and may also be related to the increased size of the adipocytes in older people.
Communication between adipose tissue and other organs breaks down
As seen in part 2, adipose tissue is more than a mere storage system. Through the signalling molecules it releases, adipose tissue plays an important role in regulating how the metabolism handles energy. One of the ways it does this is by suppressing appetite through the release of hormones like leptin. Another is by communicating with the liver and skeletal muscle, which together with adipose tissue are primarily responsible for handling all of the body’s calories. With increasing age, this signalling system starts to malfunction as adipocytes die or become senescent (a state in which they stop dividing and release inflammatory molecules). Among the resulting changes, adipocytes produce less of the satiety hormone leptin, and don’t respond as well to the hormone insulin or to signals from the central nervous system. These changes makes adipocytes less able to take up glucose from the blood, and more prone to release their lipid stores as fatty acids, which then build up in other tissues.
While the effects of ageing on adipose tissue are well established, there is also mounting evidence that a reverse relationship exists: having too much white adipose tissue can accelerate ageing and promote age-related diseases. How this happens is an ongoing area of research – after all, we are still a long way from fully understanding how humans age to begin with. Scientists have identified prominent mechanisms by which white adipose tissue might contribute to ageing.
When white adipose tissue becomes ‘full’, excess lipids must increasingly be stored elsewhere, primarily in muscle and liver tissue. This leads to insulin resistance, sustained high blood sugar and eventually type II diabetes (see part 2 for a recap).
This matters in ageing because type II diabetes and insulin resistance in general appear to promote the development of all age-related diseases. The ways in which insulin resistance contributes to ageing are complicated and various. When tissues stop responding to insulin, insulin-producing cells in the pancreas respond by increasing their insulin production. Even though insulin resistant cells don’t respond properly when it comes to absorbing glucose from the blood, excessive insulin still affects molecular signalling systems inside the cell. These systems regulate processes thought to be protective against ageing (like the repair of DNA), and these protective effects are inhibited by insulin. In line with this, studies in many animal models suggest that when the effects of insulin on these systems are reduced, either through drugs or genetic modification, the animals’ maxiumum lifespans can be significantly extended.
Insulin resistance also raises the amount of glucose in the blood, since insulin-resistant cells aren’t taking it up. This glucose can bind to proteins or lipids in the blood to form molecules called advanced glycation end-products (AGEs). These molecules can stick other proteins together, preventing them from working and contributing to the progression of age-related diseases.
The mitochondria are the power plants of the cell. They convert nutrients from our food into the universal cellular fuel, a molecule called ATP. In obesity, the mitochondria become overloaded by a surplus of nutrients. This damages the mitochondria, reducing their efficiency over time, and generates harmful molecules called reactive oxygen species, which can damage other molecules including DNA. Nutrient surplus also depletes a molecule called NAD+, which is vital for the mitochondria to function and also plays an important role throughout the cell, including in the repair of DNA. These changes may contribute to accelerating the ageing process in people with obesity – for more information about how mitochondrial dysfunction contributes to ageing, see this article.
As seen in part II, white adipose tissue generates inflammatory molecules, and in obesity, white adipose tissue becomes increasingly inflammatory, while insulin resistance and mitochondrial dysfunction also promote the production of inflammatory molecules. Some of these molecules find their way into the bloodstream to promote inflammation throughout the body – this is called systemic inflammation or background inflammation.
A sustained increase in inflammatory molecules is bad because inflammation is involved in driving pretty much every age-related disease. While LDL cholesterol may be the substance of which fatty plaques are made, inflammation is the ‘spark’ that actually causes plaques to grow in atherosclerosis. Inflammation increases the risk of cancer and helps tumours to grow and spread, damages the brain in Alzheimer’s disease, and contributes to insulin resistance and type II diabetes. See this article for more information about the link between inflammation and ageing.
While cells other than adipocytes are capable of storing some lipids, they are not specialised for the task, and quantities of lipids that adipocytes could accommodate easily quickly become toxic for non-adipocytes. This is known as lipotoxicity, and it results in disease and death of affected cells, which damages affected organs, most commonly the kidneys, liver, heart and skeletal muscle. How exactly lipotoxicity kills cells isn’t fully understood, but it seems to promote age related diseases including heart disease, diabetes and dementia.
With that, our 4 part series on adipose tissue comes to a close. We have seen how fat, whether it refers to lipids or to adipose tissue, is often misunderstood. We need to consume lipids in order to remain healthy, and we need adipose tissue to buffer the calories we consume, to regulate our appetite and energy expenditure, to keep us warm and much more. Unfortunately, when adipose tissue stops working properly in obesity or ageing, the consequences can be severe.
The intention of this series was not to provide health advice, but rather to help you understand how adipose tissue works and how it interacts with the ageing process. It’s worth mentioning that recently, there has been renewed interest into the ability of calorie restriction (reducing calorie intake significantly without causing malnutrition) to reverse many of the deleterious changes associated with malfunctioning adipose tissue during ageing. Many scientists are also interested in working out the molecular mechanisms behind the benefits of calorie restriction, and targeting them using drugs. We have reported on some of this research in the past, and will of course continue to do so for future developments. Until then, look after your adipose tissue, and it will look after you!
Adipose Tissue Quality in Aging: How Structural and Functional Aspects of Adipose Tissue Impact Skeletal Muscle Quality: https://dx.doi.org/10.3390%2Fnu11112553
Adipocyte Phenotype Flexibility and Lipid Dysregulation: https://doi.org/10.3390/cells11050882
Plasticity of adipose tissue in response to fasting and refeeding in male mice: https://doi.org/10.1186/s12986-016-0159-x
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