ageing – Drug Discovery Opinion

Insulin Growth Factor Signalling in Alzheimer’s Disease

Although family history and lifestyle choices play a role, ageing is recognised to be the largest single risk factor for Alzheimer’s disease. Progression of Alzheimer’s disease is not well understood but accumulation of toxic amyloid peptides in the brain is believed to be a significant contributory factor and much research has focussed on reducing levels of these peptides. Researchers led by a team at the Salk Institute have now asked whether slowing the ageing progress might also delay the onset of Alzheimer’s disease. The insulin/insulin growth factor (IGF) signalling (IIS) pathway regulates stress resistance, and reduction of IIS has been shown to increase lifespan in worms, flies, and mice. Although reduced IGF signalling extends the life span of mice, IGF-1 infusion has also been shown to protect mice against amyloid toxicity. To address this apparent paradox, the team crossed mice that model Alzheimer’s disease with long-lived mice that have reduced IGF signalling. The animals were found to be protected from Alzheimer’s disease-like symptoms, including behavioural impairment, neuroinflammation, and neuronal loss. Although the mice continued to produce amyloid peptides, these were found to form densely packed, ordered plaques, suggesting that hyper-aggregation of more toxic soluble amyloid oligomers may explain, at least in part, the protection conferred by reduced IGF signalling.

Although previous studies have shown that IGF-1 infusion protects mice against amyloid toxicity, the growth hormone secretagogue MK-677 (ibutamoren mesylate), a potent inducer of IGF-1 secretion, was ineffective at slowing the rate of progression of Alzheimer’s disease in human patients.

IIS reduction has been found to correlate with longevity in humans – some very long-lived people have defects in components of IIS – and the present study, which is published in the journal Cell, suggests that reduction in IGF-1 signalling may be a promising strategy for the treatment of Alzheimer’s disease.

Long-Life Immunity

The primary function of the thymus is to produce mature T-cells and to implement controls to prevent auto-immunity. Lymphocyte precursors migrate from the bone-marrow to the thymus, where they become thymocytes and subsequently mature into T-cells. Since the T-cell repertoire is generated relatively early in life, the thymus is most active during childhood, begins to atrophy around puberty, and is barely detectable in the elderly.

A team led by researchers at the Children’s Hospital of Pittsburgh have now reported knock-out mice that live 30% longer than their wild-type counterparts and in which the thymus remains intact throughout life. The scientists knocked out the gene encoding pregnancy-associated plasma protein A (PAPPA), a recently identified zinc metalloprotease that degrades insulin-like growth factor binding proteins (IGFBP). The knockout mice exhibit proportional dwarfism, similar to IGF1, IGF2 and IGF-receptor (IGFR) knockouts (although IGF1 and IGFR knockout mice are not viable).

The team suggests that the PAPPA-knockout mice benefit from reduced IGF signalling in tissues as a consequence of increased levels of IGFBPs. Indeed, maintenance of thymic structure with ageing correlated with lower steady-state levels of IGF1 in the thymus. Elderly knockout mice continued to generate new T-cells and maintained a robust immune system. Whilst the subtleties of the model require further elucidation, the work so far suggests that manipulation of PAPPA may be a route to modulation of immune competence and healthy ageing.

The study is published in full in the Proceedings of the National Academy of Sciences.

Even in Older Mice, Rapamycin Extends Lifespan

US scientists have discovered that rapamycin, first discovered in a soil sample from Easter Island, can significantly extend life expectancy in genetically heterogeneous populations of mice. Rapamycin, which is used primarily to prevent rejection following kidney transplants, is an immunosuppressant that interferes with TOR (target of rapamycin) signalling. Inhibition of TOR signalling was already known to extend lifespan in invertebrates but a similar effect in mammals had not been directly demonstrated, although calorie restriction – which has been shown to enhance life expectancy in mammals – is believed to interfere with TOR signalling. The original aim of the present study was to begin treating the mice at 4 months of age but problems in developing a suitable formulation of rapamycin meant that treatment was delayed until they were 20 months old, the equivalent of 60 years old in human terms. Although the team were doubtful that the study would still provide a clear-cut result they went ahead with dosing anyway and found that, compared with untreated animals, the maximal lifespan (age at which 10% survive) was increased by 14% for female mice and by 9% for male mice. In terms of life expectancy, this is equivalent to a 38% increase for the females and a 28% increase for the males. The disease patterns and causes of death in treated and untreated mice were found to be similar. In a separate study, rapamycin was also found to increase survival in both male and female mice when administered from the age of 9 months.

If similar effects on longevity were seen in humans, inhibition of mTOR signalling, even from age 60, could still significantly enhance lifespan, although an increased susceptibility to infections and possible risk of developing lymphoma or other malignancies as a result of immunosuppression would need to be considered.

The study is published in the journal Nature.

Anti-Ageing Claims Could Soon Be Tested Scientifically

fountain of youth Since ancient times, mankind has sought the gift of eternal youth and many have claimed to have discovered the secret. Today, despite a plethora of products promising a more youthful appearance, ways to truly defy the passage of time remain elusive – and difficult to substantiate. Although determining chronological age is straightforward, establishing physiological age has remained subjective. Research by scientists at the Buck Institute for Age Research however, could now lead to biomarkers to test the claims of anti-ageing therapies. The work was carried out in nematode worms and, by looking at changes in gene expression, the group identified a suite of genes that are actively involved in the ageing process. This is the first step towards identifying similar, irrefutable, biomarkers in humans that would provide a way of testing the effectiveness of anti-ageing therapies. The technology would also provide a way of telling whether an individual is ageing more quickly or slowly than would be expected. By extending their studies to mice, the scientists hope to be able to answer questions about the effects of environmental and nutritional factors on ageing. The work is published in the November 20, 2008 online edition of Aging Cell.

MK-677 Increases Lean Muscle Mass in Elderly

elderly man It has been estimated that most people lose between 35% and 45% of skeletal muscle in the 6 decades between the ages of 20 and 80. This progressive loss of muscle is known as sarcopenia and, combined with osteoporosis, is responsible for the loss of strength, increasing frailty, and loss of independence seen in many elderly people.

Along with lack of regular exercise, declining levels of growth hormone are thought to be linked to muscle loss. A new study published in Annals of Internal Medicine describes the effect of the orally active ghrelin agonist, MK-677, in healthy adults aged 60-81 years.

MK-677

Daily dosing with 25mg MK-677 was generally well tolerated and increased levels of growth hormone and insulin-like growth factor-1 to those of healthy young adults. Over 1 year, mean fat-free mass declined in the placebo group, but increased by 20% in the MK-677 treated group. MK-677 induced a transient increase in appetite; body weight increased by 2.7 kg in the MK-677 treated group, but by only 0.8 kg in the placebo treated group. Overall, treatment with MK-677 had a positive effect on three factors that contribute to loss of muscle mass: reduced growth hormone levels, loss of fat-free mass, and inadequate food intake. The increase in lean mass seen with MK-677 therapy did not translate into enhanced strength or function, but the researchers say that “the study sets the stage for an adequately powered clinical trial of sufficient duration in a population vulnerable to frailty”.

Farnesyl Transferase Inhibitors: a Potential Treatment for Progeria

Progeria is a very rare genetic disease characterised by dramatic premature ageing; Hutchinson-Gilford progeria syndrome (HGPS) is the most severe form of the disease. As newborns, children with progeria usually appear normal but, within one year, their growth rate declines. The children develop a distinctive appearance with alopecia, a small face and jaw and a pinched nose. They have small fragile bodies like those of elderly people and suffer symptoms typically associated with ageing, including joint stiffness and severe progressive cardiovascular disease. Affected children usually die in their early teens from complications of atherosclerosis such as heart attack or stroke.

Little research was carried out into the disease until the 1990s but it is now known that HGPS is caused by a mutation in the LMNA gene which encodes the nuclear membrane protein lamin A. Lamin A requires posttranslational farnesylation to be incorporated into the nuclear membrane; the C-terminal peptide, including the farnesyl group, is subsequently cleaved, and mature lamin A becomes a prominent component of the nuclear scaffold, affecting nuclear structure and function.
Farnesyl transferase inhibitors (FTIs), originally developed as anticancer drugs, have been shown to reduce disease significantly in animal models of HGPS. A phase II clinical trial using the FTI lonafarnib began in May 2007 and has an estimated completion date of October 2009.

A new study published in the Proceedings of the National Academy of Sciences describes the effect of another FTI, tipifarnib, in transgenic mice that develop cardiovascular disease similar to that seen in progeria patients. Tipifarnib was able to prevent, and even reverse, the cardiovascular damage in mice, giving hope that a similar effect will be seen in the patients treated with lonafarnib.

Less Protein for a Longer Life?

less protein Starting in the 1930s, a number of studies in laboratory animals have concluded that a reduced calorie diet, which delivers sufficient vital nutrients, results in a longer life and delays age-related diseases. Because of these findings in animals, many people have voluntarily adopted calorie-reduced diets in the hope of increasing longevity and improving health.

A new study has shown, however, that a nutritious low calorie diet may be less effective at prolonging life in humans. In many species, reduced function mutations in the insulin / insulin-like growth factor 1 (IGF-1) signalling pathway increase maximal healthy lifespan. Although calorie restriction in rodents decreases serum concentrations of IGF-1 by around 40%, with an accompanying beneficial effect on life span, the long term effects of calorie restriction on circulating IGF-1 levels in humans was not known.

The new study has shown that, in humans, long term calorie restriction with adequate nutrients does not lead to similar changes in IGF-1 levels. By contrast, reduced protein intake did lead to a significant reduction in circulating IGF-1. These data suggest that reduced protein intake rather than just reduced calorie intake may be important to improve health and delay ageing in humans.