Anti-Ageing: One Serve of Forever Young To Go, Please!

5. April 2016

In animal studies its been quite the trick: extending life by diet or in feed additive form. Why this is so, however, is far less clear. The relationship between cellular energy supply and ageing processes seems to include a few crucial interconnection points.

Europe – the world’s pensioner village? If one is to believe the forecasts, in ten years one in five Europeans will be more than 65 years of age. In the industrialised nations centenarians are no longer a rarity. Methuselan age is no longer reached at 99 but ten years later. Actually, one might think, it’s a blessing and a success due to good hygiene and modern dietetics that, unlike in previous centuries, more people get to experience life with their grandchildren and often with their great-grandchildren.

Repairs to the Old Timer

Unfortunately, older age is the biggest risk factor for cardiovascular diseases as well as for neuro-degenerative diseases, the most prominent representative here being Alzheimer’s disease. Those who want to slow down the ageing process regardless of their genetic base facilities need to see to it that as much as possible of their cell and body functions are maintained. They must see to it as well that low grade inflammation within the body is limited to being small scale and that the adaptive immune system be kept fit. In short: they need to keep down the risk of greater damage developing from a small defect.

Flexible fuel utilisation slows down ageing

Looking beyond all the anti-ageing campaigns and remedies that are available on the open market, there seem to exist a few proven measures for not only prolonging the life span, but to also experience the last few years in a good state of health. Animal models for ageing, ranging from unicellular organisms all the way to primates, have repeatedly confirmed that decreased food intake leads to an extended life.

However, not all laboratory animals respond equally to kilojoule restriction in their diet. Comparing for example about 40 mouse strains with one another: in particular it’s those mice which despite a diet involving 40 percent kilojoule reduction yet succeed in keeping their fat reserves which are the ones which live much longer. When these mice lose weight, it still affects mainly the white fat portion. Human muscle tissue in advanced age somewhat loses the ability to use glucose for energy provision. It may possibly be, so speculate some experts, that limiting the supply of sugar could lead to the training of cell flexibility. The option of consuming varied types of substrates, be they glucose or fatty acids, is therefore likely to prolong their lives.

Energy sensors: mTOR, SIRT and AMPK

But how do the interactions between limited availability of nutrients, the related metabolic adjustment, and longevity play out in detail? A key role in the signal chain between the controllers in these areas appears to be attributable to, among other components, mTOR (mechanistic target of rapamycin). Serine threonine kinase works as a kind of intra cellular energy sensor. Growth factors or a state of excess of amino acids activate mTOR in the cells and lead to overall metabolic adjustments and to cell growth at the given nutrient levels. Inhibition of mTOR delivers the faculty to prolong life which is present in many animal models. Thus, this enzyme appears to occupy a central position in the coupling of “ageing” and power supply.

The same applies to sirtuins. They play a role in NAD-dependent deacetylation of histones and non-histone proteins. One of seven family members, SIRT1 is – at least in mice – regulated by food supply. In looking at mice with overexpression of SIRT1 in the brain, scientists saw few age-related changes in mice with aged mitochondria. These rodents were still active in their final phase of life, with a corresponding urge to move and corresponding oxygen consumption.

An important role in the energy-lifetime coupling is ultimately also played by AMPK (adenosine monophosphate-dependent-kinase). In the event of intracellular ATP depletion the cell ensures that storage molecules with lower energy content such as ADP and AMP are also available. AMPK down-regulates power consumption in the cell and ensures economic resource utilisation. Overall, a number of other – in particular mitochondrial – proteins, appear to directly or indirectly influence the life span. Reactive oxygen radicals – previously decried as cytotoxins – according to the latest findings even promote longevity. Perhaps also because they are the impetus for renewal of cell organelles.

Immunosuppressant and red wine extract

How do things look now in the clinic? Given that we find out precisely where we need to attack, the pathway which leads to the respective medication should not be too far out of reach. Resveratrol – the well-known red wine polyphenol – is one of the most renowned, and also most discussed, activators of SIRT proteins. Curiously resveratrol extends the life of mice on energy-sparse diets as well as those given excessively high energy food – yet this is not the case for “normally” fed animals. Human studies indicate that resveratrol is effective against calcification of coronary arteries and especially with overweight people ensures a more active metabolism and improved muscle function. How it does so, however, is not yet clear.

Rapamycin was named by the US National Institute of Aging as a promising ageing cure. The active agent, originally obtained from bacteria, has long been considered an immunomodulator used in association with organ transplants and in the treatment of kidney tumours. Used on mice, doses of rapamycin prolong longevity, especially with female mice, by 10-20 per cent, presumably due to the mTOR complex’s inhibition properties. Short-term treatment weakens the immune system and lowers insulin levels. With prolonged treatment however, insulin sensitivity improves and the metabolism is stimulated. The vigilance of the immune system also benefits from this. Whether rapamycin leads to long healthy life for human pensioners will probably be shown in the next few years. Before that experiments on monkeys would have to at least confirm the good results obtained with mice.

Anti-ageing by recipe?

Metformin, previously made known by use as an active agent for diabetics, also has similar effects to those brought about by kilojoule restriction. Mice in advanced age at least live not only longer and healthier lives with metformin, but are also less prone to cancer. Higher doses are harmful, small amounts of metformin in contrast induce more AMPK activation, better uptake of glucose and more effective oxidation of fatty acids. Whether this is also true for humans is something being tested at the moment by the TAME study (targeting ageing with metformin). Metformin-taking diabetics at least have a reduced risk of cancer. The organisers of the TAME study admit openly that they want to convince the American FDA to recognise ageing as a disease that is able to be treated with pharmacological agents.

Intervention in insulin metabolism is apparently closely linked to the ageing process. A decreased signalling from insulin/IGF-1 (insulin-like growth factor 1) is also associated with the life of a laboratory mouse gaining extra days.

Ageing is an individual process

It is still relatively unclear to what extent all these metabolic nodes are interconnected and interdependent. In all probability the testing of anti-ageing-agents on any one certain marker of the ageing process in reality misses the mark. For example, muscle degradation in humans sets in rather early in the course of life, whereas diminished mental capacity can be detected only very late. Increase in the proportion of fat as part of body weight is ultimately highly variable in individual terms. 

Many of the mentioned active agents tested out via animal experiments unfortunately have massive side effects. Rapamycin impairs vision and leads to a degeneration of the testicles.

Multimodal approaches needed

Ageing, in contrast to well described oncological or neurological diseases, is no clearly defined process which can be accurately studied based on typical symptoms. Already when using inbred mice and standardised food, study results show an enormous variability that is even reflected to some extent in some animals in a shortened life span. The lack of suitable biomarkers in the pathological ageing process has so far prevented advances in anti-ageing making their way into the clinic. One development that focuses on one single metabolic step is hardly likely to lead to a universal ageing postponer.

Nevertheless, when it is possible to maintain repair operations and preserve spare replacement parts in the body as long as possible, if we can manage to maintain the attentiveness and diligence of the immune system beyond age 70, then we would have a good anti-ageing-strategy. Many disorders don’t raise their heads until well into the second half of life. When it is possible to recognise and treat even before they appear in their advanced form, this would probably not only prolong life, but also lead to ageing which meets our desires.

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1 comment:

David Wiggin
David Wiggin

I really want to live to a healthy old age but am totally fed up with it being reliant on animal studies, “all the way to primates”. When we learn to stop this atrocious behaviour for the sake of 1 miserable species?

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