Potentially conserved pro-ageing pathways, their interconnections and possible targets for intervention

PubMed Central, Figure 1: Nature. 2008 August 28; 454(7208): 1065–1071. doi: 10.1038/nature07216 from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2774752/

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In this very simplified depiction, three main pathways, the IIS (insulin/insulin-like growth factor 1 (IGF-I) signalling) pathway, TOR and mitochondrial pathway, are indicated.

The pro-ageing activities of these pathways are conserved across species, with energy sensors, such as AMPK, as potentially important hubs in the complex networks that integrate them.

However, it is important to note potential dissimilarities among species as well. Most, if not all, defects in the mitochondrial respiratory chain are lethal or cause disease in humans, but can increase lifespan in nematodes or yeast. In mammals, mitochondria play an important part in signalling apoptosis, which can either drive or retard ageing, depending on the cell type.

There is evidence that many longevity signals converge on members of the FOXO and sirtuin protein families, which can interact. Effects of FOXO and SIR2 in cells can be either beneficial (for example, increasing antioxidant defence) or detrimental (for example, apoptosis), and may or may not promote organismal survival. Apoptosis can be beneficial, for example, by eliminating damaged cells and preventing cancer, or can be detrimental, by eliminating irreplaceable cells, such as neurons.

Emma Rourke reviews Horizon: Eat, Fast, and Live Longer

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14 Aug, 12 | by BMJ Group

There’s a new intervention being trialled. It will help you lose weight, it will delay the potential onset of dementia, and best of all it will enable you to live in the fullest of health for longer. Perhaps the main virtues of this intervention centre on its sheer simplicity: it doesn’t involve putting any chemicals into your body, it doesn’t involve surgery, and it doesn’t cost anything—it may even save you money. All you have to do is deprive yourself of one of life’s great pleasures—food.

The BBC aired Horizon: Eat, Fast and Live Longer earlier this week. During this one hour programme, Michael Mosley visits a number of institutions seeking to understand the ageing process. He meets a variety of experts, all of whom extol the virtues of caloric restriction (CR), and tries methods they advise in attempts to improve his performance on physiological testing. The most extreme of these methods involved 3 days and 4 nights of fasting, wherein Mosley consumed only water, black tea, and a single sachet of powdered soup.  Subsequently, he tried alternate day fasting, where consumption is limited to around 500 calories on one “fast” day and completely unlimited the following “feed” day. He finally settled for a 5 day “feed” period followed by a 2 day 500 calorie fast period.

For a supposedly scientific programme, however, the science was rather scant. The focus was strongly on the insulin-like growth factor 1 (IGF-1) as mediator of the benefits of CR. This signalling pathway has been widely studied and is known to stimulate growth and inhibit apoptosis of cells. Perhaps unsurprisingly given this role, it has been implicated in the pathogenesis of cancer [1]. It has several key functions in the body, including growth and maintenance of the skeletal system [2]. Interestingly, in vivo deficiency of IGF-1 in combination with testosterone correlates with reduced survival [3].

CR (without malnutrition) has been shown to increase lifespan in laboratory animals. In rodents, for example, CR postpones onset of age-related pathology and prolongs lifespan [4]. Is this explained solely by IGF-1 levels? Studies have sought to test the popular oxidative stress theory of ageing, and indeed noted reduced markers of oxidative damage in calorie restricted rodents [4]. This alternative mechanism by which CR may affect ageing is not even touched upon by the programme. As with much human science, it is more complicated than it seems and there is still no consensus on the role of antioxidant levels in CR—there’s something else at play [4]. That something may involve the nutrient-sensing pathways of target of rapamycin (TOR), it may involve the forkhead transcription factor (FOXO), and it may involve sirtuins [5]. In fact, the one thing we can be sure about is that the molecular determinants of lifespan are incredibly complex, and far from fully understood [6].

The programme furthermore neglected many social factors complicit in the ageing process. Humans are not laboratory animals and their environment cannot be so strictly controlled. Nevertheless, somewhat controversial experimentation in humans is ongoing. Accordingly, some may question whether it is responsible for a qualified doctor to so emphatically endorse such an approach in a prime time television slot? “This could radically transform the nation’s health,” he says.

The programme was littered with health warnings—“don’t do this without supervision” and “for some fasting can be dangerous”—but within hours online weight loss forums were overflowing with posts from people saying they’d give it a go. Mosley’s wife, a GP, appears to support his desire to pursue a 5 days feeding 2 days fasting regime, thus reinforcing to the public that this is a safe and worthwhile method.

Perhaps the diet Mosley ultimately adopts is not that radical, and perhaps it doesn’t even represent CR (the level at which CR is defined varies from 10-25% reduction in overall calorie intake in humans). Any attempt to encourage reduced calorie intake in a nation with such high rates of obesity as our own may be commendable, but critics will likely find little new in the advice Mosley dishes out: reduce your calorie intake, reduce your weight, reduce your cardiovascular risk factors. Perhaps that’s the message to hope people take forward from this.

References:

[1] Hematol Oncol Clin North Am. 2012 Jun;26(3):527-42, vii-viii. Epub 2012 Feb 28.

[2] J Bone Miner Metab. 2008;26(2):159-64. Epub 2008 Feb 27.

[3] Steroids. 2012 Jan;77(1-2):52-8. Epub 2011 Oct 20.

[4] Mechanisms of Ageing and Development. 2004;125(10-11):811-26.

[5] Nature. 2008;454(7208):1065-71.

[6] Free Radic Biol Med. 2011 Jul 15;51(2):250-6. Epub 2011 Apr 22.

Worm lifespan doubled - Cynthia Kenyon

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Refs: Unlocking the Secrets of Longevity Genes; March 2006; Scientific American Magazine; by David A. Sinclair and Lenny Guarente; 8 page(s)

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