PharmacoNutrition Reviewed

I don’t know whether many of you already read this article. As it is not (yet?) listed in the PubMed and has been published in a rather new journal (Current Aging Science) most probably not.
Anyway, I very much liked reading the review by Alberto Sanz and Rhoda Stefanatos (University of Tampere, Finland) which again deals with the pros and cons of the Mitochondrial Free Radical Theory of Aging (MFRTA).

“The Mitochondrial Free Radical Theory of Aging (MFRTA) proposes that mitochondrial free radicals, produced as by-products during normal metabolism, cause oxidative damage. According to MFRTA, the accumulation of this oxidative damage is the main driving force in the aging process. Although widely accepted, this theory remains unproven, because the evidence supporting it is largely correlative. For example, long-lived animals produce fewer free radicals and have lower oxidative damage levels in their tissues. However, this does not prove that free radical generation determines life span. In fact, the longest-living rodent -Heterocephalus glaber- produces high levels of free radicals and has significant oxidative damage levels in proteins, lipids and DNA.

In summary, available data concerning the role of free radicals in longevity control are contradictory, and do not prove MFRTA. In fact, the only way to test this theory is by specifically decreasing mitochondrial free radical production without altering other physiological parameters (e.g. insulin signalling). If MFRTA is true animals producing fewer mtROS must have the ability to live much longer than their experimental controls.”

The full text article is available here.

Source: Journal of Gerontology (Biol. Sci.) 63A (2008): 242-252
Article Type: Original Research
Authors: I Lenaerts et al.

When working with C. elegans myself (limited times though) I didn’t break my head too much about the pros and cons of feeding them with heat-inactivated E. coli as long as each plate contained the same amount of food.
Well, I maybe should have given it another thought, at least based on the latest article by Isabel Lenaerts and colleagues.

Here, the authors “…describe convenient ways to exert DR (dietary restriction) by culture on agar plates containing axenic (i.e., there is no microbial food source) medium. We used these to explore whether effects of axenic culture really reflect DR. Our results imply that major nutrient components of axenic medium, and overall caloric content, are not limiting for life span. However, adding growth-arrested Escherichia coli as an additional food source rescued the effects of axenic culture. We then sought to identify the component of E. coli that is critical for normal C. elegans nutrition using add-back experiments. Our results suggest that C. elegans has a nutritional requirement for live, metabolically active microbes or, possibly, an unidentified, heat-labile, nonsoluble component present in live microbes.”

Of note also, the addition of Daucus carota and Pisum sativum extracts to axenic medium, e.g., increased fecundity without affecting lifespan. In contrast, increasing concentrations of autoclaved or sonicated E. coli had no effect on offspring number.
Also, radiation-arrested but metabolically active E. coli rescued the effect of axenic medium. This, however, was just seen for low-dose radiated E.coli, indicating that “…as long as some metabolically active E. coli remained, rescue was possible. This finding suggests the surprising conclusion that metabolic activity in its microbial food source is a nutritional requirement for C. elegans.”

Almost everything known regarding C. elegans can be found here: wormbook.org

Source: BMC Medical Genomics (Open Access, 20 March 2008)
Article Type: Original Research
Authors: Pan Z et al.

Pterostilbene, a dimethylether analog of resveratrol, has long been known for its antioxidant, antifungal and antiinflammatory activities (to mention just a few). However, little is known on its mechanism(s) of action. In the present study, Pan et al. incubated S. cerevisiae (a common model organism for the identification of therapeutic compounds) with 70 µM (= IC50) pterostilbene prior running extensive transcript profiling experiments.
In a nutshell, pterostilbene affected the expression of >1000 genes (up: 1007; down: 182).

“We have identified the molecular pathways affected by pterostilbene, and our results show that pterostilbene affects the expression of a diverse group of genes in yeast cells.Using Gene Ontology-based analysis, the most significant effects were observed in genes involved in methionine metabolism, response to drug, transcription factor activity, and mitochondrion functions. Additional analyses indicated that many genes involved in lipid metabolism were also affected. The observed response of lipid metabolism genes is in agreement with the known hypolipidemic properties of pterostilbene mediated through the activation of PPARalpha. The induction of a large number of mitochondrial genes by pterostilbene is consistent with its previously-demonstrated role in apoptosis in human cancer cells.Our data also show that pterostilbene has a significant effect on methionine metabolism, perhaps resulting in the depletion of methionine by the inhibition of methionine biosynthesis. The effect of pterostilbene on methionine metabolism has not been previously observed and merits further investigation.”

The effects on methionine might be of particular interest, as methionine metabolism has also been linked to aging.
Does this possibly mean that resveratrol and its analogs enhance, e.g. C. elegans, lifespan by modulating methionine levels? PubMed, at least, does not provide a sufficient answer….

Source: Am. J. Physiol. Regul. Integr. Comp. Physiol. (2007) [Epub]
Article Type: Original Research
Authors: Martin-Gronert et al.

This is now the third time I am writing about the impact of in utero and early postnatal nutrition on fitness in later life.  Whereas before we learned some new insights in how changes in maternal dietary iron or fat might affect offspring life, the new paper by Martin-Gronert et al. addresses the question how dietary postnatal protein levels regulate key molecules believed to markedly control the aging process.

When pups of normally-fed dams were nursed by low-protein-fed (8% vs. 20% in the control group; iso-caloric diets) dams, dramatic biochemical changes (measured at day 21 post partum) occurred that might explain the earlier reported increased lifespan in these animals. The authors not only found that insulin sensitivity was improved but also a significant upregulation (measured in kidney tissue) of IRbeta, IGF1-R, Akt1, Akt2 as well as SIRT1. In addition, the expression of important antioxidant enzymes, i.e. catalase, CuZnSOD and GPx1, was elevated.

Martin-Gronert et al. conclude that “the findings of this study are in agreement with Hormesis Hypothesis, which has been proposed to explain the life-extending action of calorie restriciton. The hypothesis postulates that a low-intensity biological stressor exerts defence responses in the organism that help protect it against the causes of aging. The enhanced coping with intense stressors and restriction of senescent deterioration lead to retardation of age associated diseases and increased longevity. It seems that a similar process may underlie the association between early nutrition and the aging process.”

A candidate for the effect of restricted protein intake on lifespan has also been recently identified by Naudi et al.: methionine (whose restriction leads to upregulation of uncoupling proteins (UCP4) and an increase in mitochondrial biogenesis).

Poor mums-to-be: your burden of doing things right during pregnacy and nursing are certainly on the rise.

Image taken from: jupiterimages.com

Source: Science 317: 516-519
Article Type: Original Research
Authors: Outeiro et al.
As members of the histone deacetylase family of proteins, sirtuins play a prominent role in aging. Seven sirtuins, SIRT1 to SIRT7, have been identified in humans.
Most research on sirtuin-mediated modulation of life span focussed on the activation of sirtuins (especially SIRT1), e.g. via resveratrol, a stilbene present in red wine and other food plants.
In the July 27 issue of Science, Outeiro et al. now report on the rescue of alpha-synuclein-induced neurotoxicity in models (cell cuture and Drosophila m.) of Parkinson’s disease (PD) due to inactivation of SIRT2. The mechanism of action might be due to 1) alterations in alpha-synuclein aggregation and 2) microtubule stabilization. Whether SIRT2 inactivation also directly affects life span, however, has not been addressed in this article. Those interested in this aspect might want to have a look at a recent paper published by Wang et al. (Aging Cell 6(4), 2007), where the authors descibe elevated SIRT2 expression in response to caloric restriction, a classical ‘inducer’ of longevity.

If you are looking for more information on PD, have a look at the PD Blog Network.

Image taken from: www.pdmdcenter.com

While I am still struggling to digest Richard Dawkins’ “Ten Commandments” raised in his new book “The God Delusion”, I just found on Ouroboros - Research in the Biology of Aging a hint regarding another list of “Ten Commandments”, this time for the future of aging research in the UK.
As I am particularly interested in diet & nutrition, the 6th commandment caught my attention as is states the word “nutrient” in connection with an individuals’ genetic make-up and response to enviromental impact.
The original article is freely availabe at BMC Geriatrics.

Source: Neurobiology of Aging (2007), in press
Article Type: Original Research
Authors: A Bender et al.

Image taken from: http://www.scienceinafrica.co.za/pics/06_2004/brain.jpg

Creatine (an amino acid derivative) is a widely used food supplement due to its putative ergogenic, i.e. exercise capacity enhancing, effect. In terms of exercise performance, a recent review by Paddon-Jones and colleagues (J. Nutr. 134) concludes that creatine is suggested to be of benefit to exercise lasting 30 seconds or less; in contrast, no direct effect of creatine supplementation on muscle protein synthesis has been found. Nonetheless, creatine sales still reached US$ 220 million in 2005.
So whereas creatine might do rather little to improve exercise performance, it still seems to improve health. And not only this, but also survival – at least in mice. Based on previous reports demonstrating protective effects for creatine in models of neurodegeneration, Bender et al. tested the hypothesis whether creatine might also facilitate healthy aging, particularly of the brain, in wild-type mice. In essence, feeding mice a diet containing 1% creatine from 12-month of age onwards, significantly increased both mean and maximum life span in comparison to control mice. Somewhat confirming what was said already above, the creatine-fed mice did not differ in the rotarod and grip strength analyses; however, creatine feeding improved (p<0.05) several markers of memory performance such as object recognition. Also, biomarkers of brain aging due to oxidative stress tended to be lower in the creatine-fed group. Based on gene expression profiling experiments, the authors conclude that creatine not only reversely regulates gene expression altered in aging, but also concordantly affects gene expression as in mice on caloric restriction. Whether this effect of creatine is due to the induction of mild stress like in the case of caloric restriction is unknown. Another potential mechanism of creatine-induced neuroprotection might be the prevention of ROS (recative oxygen species) generation due to enhanced activity of mitochondrial creatine kinase activity, as recently shown by Meyer et al. (JBC 281).
In light of the rather minor safety concerns raised regarding creatine supplementation, it might be worth to further explore the potential of this amino acid derivative to improve healthy aging.

Source: Biogerontology (200), 7: 307-314
Article Type: Review
Authors: V Frazzini, E Rockabrand, E Mocchegiani, SL Sensi

Image Taken From:
http://upload.wikimedia.org/wikipedia/commons/thumb/7/79/
Zinc_finger_DNA_complex.png/300px-Zinc_finger_DNA_complex.png

Zinc (Zn) is the second most abundant trace element in the body (total amount approx. 2 g) and essential for human survival. Zics’s role in human physiology include a) catalytic (about 300 enzymes are Zn-dependent), b) structural (‘Zn-finger motifs in proteins) and c) regulatory (metallothioneins, immunes response, insulin metabolism) function.
Currently, a daily Zn intake of 10 mg is considered adequate. Dietary surveys showed widespread, worldwide prevalence of inadequate Zn intakes with, however, considerably lower risk in North America and Europe than other parts of the world.
Well-known clinical Zn-deficiency symptoms include a) skin lesions & delayed wound healing, b) immune deficiency, c) impaired taste and appetite and d) eye lesions. Consequently, Zn is nowadays commonly found in dietary/food supplements.

As with any nutrient, too much is too much. This brings us to the recent article by Frazzini et al. who asked the question whether Zn could actually be a link between oxidative stress and brain aging.
What caught my interest are the in nerve cells observed regional differences of Zn dysregulation, which have been suggested to trigger ‘normal’ brain aging and especially neurodegeneration.
The figure below summarizes the key aspects of the mechanisms possibly explaining Zn’s potential to induce brain cell death.

Does this now mean we should be aware of our daily Zn intake to protect our brain?
Most probably not. Although Zn toxicity (here especially peripheral symptoms) has been described in individuals repeatedly consuming more than 50 mg per day, the blood brain barrier, which regulates Zn homeostasis of the brain, is comparatively impermeable to changes in the concentration of blood metal ions. This does, of course, not mean that one cannot deplete the brain of Zn when significantly cutting down oral Zn intake.
In terms of neurodegeneration, for example Alzheimer’s disease, current believe is that the toxic effects of Zn are due to disruption of the brain endogenous Zn homeostasis, a hypothesis which is supported by studies in neuronal-specific Zn-transporter knockout mice.

As a general comment, I think Zn deficiency is a far bigger problem that chronic Zn overload for the majority of people. So, despite the increasing number of studies linking brain Zn with neurodegeneration, the above mentioned facts hopefully made clear that there’s only little - better to say no - hope of preventing neurodegeneration by reducing Zn intake. Vice versa, increase Zn intake above the current RDA to boost the body’s antioxidant and subsequently disease resistance, as suggested in various publications, must also be discouraged due to lack of evidence.

FIGURE: Mechanism of Zn-mediated Neurodegeneration

Source: Trends in Neuroscience (2006), 29: 632-639
Article Type: Review
Authors: MP Mattson, A Cheng

Image taken from: http://www.bad-bad.de/gesch/paracel.gif

Recently, the hormesis theory is gaining momentum for explaining the health-beneficial effects of diets rich in fruits and vegetables. Actually, one of the first to describe hormetic effects of any substance applied to living things has been Paracelsus, one of the most famous scientists of the 16th century.
What is hormesis? The term describes the induction of health-beneficial effects due to the low-dose presence of agents that are toxic at higher concentrations (adaptive response). In this regard, phytochemicals (such as polpyhenols) can be considered as mild stressors provoking the up-regulation of the endogenous antioxidant network. This in turn would enable an organism to better cope with an increasing production of reactive oxidative and nitrosative species (ROS and RNS), for example in disease states. Consequently, the detrimental degeneration of proteins, fatty acids, sugars and DNA would be avoided. In the long run, this could finally lead to a healthier aging process, characterised by a lower burden of chronic, lifestyle maladies. Mattson and Cheng support this concept by summarising recent data obtained with, amongst others, the neurohormetic phytochemicals resveratrol and curcumin in vitro and in vivo.

Personally, I feel quite comfortable with this theory. However, whether it will help to answer the recurring question of whether an increase/decrease in biomarkers such as antioxidant capacity or antioxidant enzyme activity upon incubation/intake of phytochemicals is actually beneficial or detrimental, only time will tell.

For further reading, I recommend: Arumugam et al., 2006 and Hipkiss, 2006 and Hayes, 2007.

Source: Aging Cell (2007), 6: 15-25
Article Type: Original Contribution
Authors: TG Valencak, T Ruf

Image taken from:
http://www.macvillage.de/blog/wp-content/uploads/2006/07/dali_zeit.jpg

Omega-3 fatty acids (n-3) are generally considered as health-beneficial (see also post discussed yesterday). When talking about the lifespan of mammals, however, n-3 fatty acids seem to hamper longevity. The reason for this correlation has been linked to:
• the high susceptibility of polyunsaturated fatty acids (PUFA; n-3, n-6) to oxidation
• the boost in basal metabolic rate (BMC) in the presence of PUFA, e.g. by up-regulating the activity of membrane-associated proteins
These effects have been summarized in the ‘membrane pacemaker theory of aging’: PUFA (up) –> BMR (up) –> longevity (down).

After correcting for body weight and phylogenetic effects, Valencak & Ruf found a clear correlation between the ratio of n3:n6 in muscle and maximum lifespan (MLS), based on the analysis of 42 mammalian species. Noteworthy, MLS was unrelated to docosahexaenoic (DHA, n-3) content, total membrane unsaturation as well as BMR, thus questioning the ‘membrane pacemaker theory of aging’.
Does this mean now that we should avoid consuming PUFAs, particularly n-3?
I would say no, because the current recommendation (see also Simopoulos, 2006) to increase dietary n-3 intake is largely based on the discrepancy in the composition of ingested dietary fat between western societies (n-3:n-6 = 1:15) and our hunting & gathering ancestors (n-3:n-6 = 1:1). Hence, the risk of reducing your (maximum) lifespan by consuming n-3-rich plant and animal foods (which consequently will enhance your n-3:n-6 ratio) is rather small.