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Anti-Ageing is still a far-off dream

Is it possible to halt the ageing process? This question was first raised in the 1980s when researchers succeeded in delaying the ageing process in threadworms by modifying a specific gene. Nowadays, hundreds of gene mutations are known to prolong the lifespan of yeast, fruit flies and mice. Will the human dream of eternal youth eventually become reality? The truth is, probably not. The vast majority of researchers in this field are working on the far more realistic issue of ensuring a long and healthy life – a vital issue in the light of demographic changes.

The finding that the length of life of yeast, fruit flies and mice can be prolonged could give rise to hopes that tiny molecules, either in the form of nutrition or pharmaceuticals, may be used to manipulate ageing-related biochemical reaction channels on a genetic level. Optimists might see this as the first of many steps towards human application. But caution needs to be exercised because what prolongs the lifespan of yeast might not necessarily work for humans.
There is growing evidence that shows it is impossible to halt ageing. One such example is the insulin signalling pathway. Whilst invertebrates have a receptor which binds ligands that are similar to those of insulin and the insulin growth factor (IGF), mammals have different receptors for insulin and IGF-1 that are used in different, although overlapping, functions. IGF-1 predominantly controls mammalian growth while insulin regulates the mammalian metabolism. Defective insulin signalling pathways lead to insulin resistance and diabetes, protein degradation and muscle degeneration. On the other hand, the overexpression of IGF-1 reduces age-related cardiac disorders and improves muscle formation.

The complex interaction of sirtuin and Fox proteins has been investigated in many species, including humans. But it is still not known whether these proteins actually increase or reduce the longevity of mammals because mammals require apoptosis and senescence in order to be able to suppress cancer. This is not the case in yeast, fruit flies or threadworms which are organisms that never or hardly ever develop cancer.

The search for “ageing genes“

Many researchers regard the intervention with evolutionarily conserved ageing processes in experimental animals as a realistic step along the way to finding out how to prolong human life. But it is still not known whether these biochemical processes have an impact on human ageing. Initially, the connection between polymorphisms of and around conserved genes and human longevity would need to be determined.

In the search for such “ageing genes”, researchers have found variants of highly active genes of the lipoprotein metabolism; Fox1 and Fox3 gene variants have also been associated with long life.

The problem of complex organisms

Sceptics believe that the complexity of human organisms restricts the efforts to halt ageing as they interfere with metabolic mechanisms. This sceptical view would appear to be supported by two long-term, ongoing studies involving primates. (Preliminary) results of long-term studies on rhesus monkeys living a calorie-restricted diet are not unequivocal.

Evolutionary logics of ageing

Before researchers can seriously think about how to intervene to prolong life, they need to achieve an understanding of why and how humans age. It appears to be generally accepted that ageing is the result of evolutionary processes. In sexually reproducing species, the strength of natural selection gradually decreases as adults age.

Due to huge differences in lifespan between different organisms, some researchers believe that longevity was built up as part of the evolutionary process through gradual modifications in a large number of genes rather than through individual mutations with major effects. Such individual mutations would prolong life but this would be at the cost of the ability to reproduce or to survive under stress.

Little is known about the direct causes of death

Wrinkled skin is a typical sign of old age. (Photo: University Hospital Ulm) © UK Ulm
Relatively little is known about the direct causes of ageing and its relationship with diseases that lead to death. This is most probably due to the varied appearance of ageing and the difficulty in determining age. Researchers know a lot about life-prolonging genes, but little about the causes of death of experimental animals. About 20 age phenotypes reveal similarities between humans and the classical model organisms, but at the same time there are also considerable differences.

Cellular ageing (senescence) was previously regarded as the ageing model of organisms; nowadays, cellular ageing is regarded as the body’s response to stress and tumour suppression. Cell ageing increases as mice, primates and humans age, but only involves part of the cells in renewable tissue. There is scientific evidence that cellular senescence evolved as a mechanism to prevent the onset of cancer in the early phase of life. On the other hand, cellular senescence also seems to speed up the ageing process by exhausting stem cells or changing their niches.

Ageing cells secrete inflammatory cytokines and other molecules that change the environment around the tissue and potentially boost the growth of cancer precursor cells. On the other hand, increasing senescence and a reduction in the growth potential might also explain why the cancer rate decreases as an organism reaches old age.

The difficult relationship between disease and ageing

Researchers are currently debating whether it makes sense to differentiate between disease and ageing. However, this can only be answered on a case by case basis, as it depends on the type of disease and on how the disease mechanisms are linked with intrinsic ageing. The father of ageing research, Leonard Hayflick, hints at numerous non-pathological signs of old age, such as grey hair or wrinkled skin; he clearly separates the ageing process from diseases, but also sees it as a consecutive relationship, because ageing increases a person’s susceptibility to disease.

The ability to successfully treat typical old-age diseases such as arteriosclerosis, diabetes, dementia, osteoporosis, osteoarthritis and cancer does not mean that this has an effect on the intrinsic ageing process and considerably increases a person’s lifespan.

Many independent causes

Ageing is influenced by genetic and external factors that are not related to each other or to the intrinsic ageing process. Relatively early in an organism’s life, (epi-) mutations lead to genetic diversity. In a similar way, environmental factors linked to lifestyle can accelerate intrinsic ageing in certain tissues. It is still not known whether there are intrinsic ageing mechanisms that affect all cells or tissues and the basis of intrinsic ageing also remains unknown.

Intrinsic ageing

A universal intrinsic ageing process might explain common age phenotypes in animals: the lifelong accumulation of all kinds of damage along with accidental mistakes in the bioinformational process. Many researchers see ageing as the accumulation of a number of disorders on the molecular level, in other words as a stochastic process, which begins after sexual reproduction and gets out of hand, outrunning the body’s repair and metabolic mechanisms and combined with a growing susceptibility to disease.

The attenuation of such damage might explain the longevity that can be achieved through mutations that slow down normal metabolic processes. In addition, the defence system which keeps the damage in check, might be more efficient in one species than another.

Under suspicion: oxygen radicals and reduced sugars

Oxygen radical formation of old fibroblasts (fluorescent detection). (Photo: University Hospital Ulm)
Highly reactive oxygen radicals (ROS) and reduced sugars are repeatedly linked with molecular ageing. ROS, which result from cellular respiration, might damage genes, proteins and fats and cross-link with each other. Reduced sugars react with carbohydrates, freeing amino acid residues and leading to advanced glycation end products (AGEs) which are difficult to degrade and which accumulate in long-lasting structural proteins such as collagen and elastin. They harden blood vessels, joints and the bladder and impede the function of the kidneys, heart, retina and other organs.

A popular hypothesis assumes that interventions to counteract ROS and AGE lead to the indefinite delay of the ageing process. However, the problem is that such macromolecular damage occurs in different forms and that their mutual contribution to intrinsic ageing has still not been clarified. Caution needs to be exercised because some of these “dangerous” molecules, for example glucose and ROS, are important for the cells as they also function as signalling molecules.

Fragile balance

The fact that some of these molecules have "good" and "bad" effects might make life-prolonging strategies even more difficult. Let us have a look at the cellular mechanisms that protect us against cancer. Cancer risk increases as tissue is renewed; the risk of DNA mutations and epimutations increases either as a result of mistakes occurring during DNA repair or because of the amplification of damaged DNA regions.
Tumour suppression mechanisms eliminate severely damaged cells through apoptosis and by stopping their growth (senescence). This could eventually lead to the loss of tissue, loss of organ function and the loss of regenerative ability. In principle, stem cell transplantation may be able to counteract these adverse effects.

Some researchers working on ageing speculate that more serious consequences occur if the damage is not severe enough to induce apoptosis or senescence: the gradual accumulation of accidental gene or protein modifications turns the tissue into cellular mosaics. It would be difficult to correct this stochastic drift in gene regulation, which could equally happen in in-vivo stem cells or in ex-vivo stem cells as they expand prior to transplantation.

Strategies against intrinsic ageing

No anti-ageing experiments, whether they involve resveratrol, fisiten or rapamycin, ever produce clear-cut results. The glucose metabolism is one of the major targets of life-prolonging interventions: as it has been proved possible to prolong the lifespan of animals living on a calorie-controlled diet, it is also hoped to achieve the same effect by reducing the energy metabolism or by down-regulating the insulin pathway in humans. It is not known whether a mimetic drug such as 2-desoxy-D-glucose (2DG) has a life-prolonging effect.

Although in humans, the consumption of dietary anti-oxidants seems to be correlated with reduced risk of disease, clinical trials involving vitamin E and ß-carotin did not show any effect. Similar results have been obtained with radicals such as phenyl-tert-butylnitrone (PBN) which block or reverse damage in animal models and which have been associated with several diseases. So far, PBN has not shown any life-prolonging effect in mice.

Alternative: Cell substitutes

Progress in stem cell research makes cell substitutes a promising therapy for regenerating intrinsically altered, functionally impeded tissue. However, little is still known about many things: how adult stem cells contribute to the preservation of the tissue during ageing, how the ageing process affects the microenvironment or the stem cell niche and how well the ability of stem cells to regenerate functional tissue during differentiation and expansion can be maintained in culture.

The problem of translation

The expectations placed on pharmacological interventions on the basis of pathways identified in model organisms might turn out deceptive. Progress in the search for longevity seems to decrease with the growing complexity of organisms as well as depending on the specific physiology of an organism. It also seems that the lifespan of some organisms is less plastic than that of others. The phenomenon of cancer is in direct opposition to longevity. Cancer clearly differs from age-related degeneration and can be suppressed by mechanisms which in turn have a life-prolonging effect.

How do metabolic processes work?

In addition, there are considerable gaps in the understanding of how our metabolic processes work and interact with each other. It is also not known whether it is macromolecular damage alone that causes us to grow old. Indeed, there is evidence that ageing is a kind of accidental gene expression pattern that cannot be counteracted with pharmaceuticals or biological interventions.

Correlative or causal?

In order to be able to assess the effects of interventions against ageing, it is necessary to understand the relationship between the pathogenesis of age-associated diseases such as cancer, diabetes or Alzheimer’s and basic molecular processes. It seems plausible that many disease risk factors depend on ageing, which in turn seems to depend on more than just one cause. The clarification of these relationships might move us one step further on in our understanding of ageing.

wp, 20 November 2008
© BIOPRO Baden-Württemberg GmbH
Literature (selection):

Vijg, Jan; Campisi, Judith: Puzzles, promises and a cure for ageing, in: Nature, vol. 454, 28 August 2008, p. 1065-1071. (doi:10.1038/nature07216)

Partridge, Linda; Gems, David: Benchmarks for ageing studies, in: Nature, vol. 450, 8. November 2007, p. 165-167.

Hayflick, Leonard: Biological Aging Is No Longer an Unsolved Problem, in: Annals of the New York Academy of Sciences 1100: 1-13 (2007).(doi:10.1196/annals.1395.001)

Rose, Michael R.: Lässt sich das Altern aufhalten? In: Spektrum der Wissenschaft. Dossier 04/08: Langlebigkeit

Behl, Christian: Molekulare Grundlagen des Alterns – eine Einführung. In: Ganten/Ruckpaul (Ed.), Molekularmedizinische Grundlagen von altersspezifischen Erkrankungen, Berlin Heidelberg 2004, p. 67-86.
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