Prolonged Intake of Coenzyme Q10 Impairs Cognitive Functions in Mice.

J Nutr. 2009 Aug 26.

Sumien N, Heinrich KR, Shetty RA, Sohal RS, Forster MJ.

Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer’s Disease Research, University of North Texas Health Science Center, Fort Worth, TX 76107.

Coenzyme Q(10) (CoQ(10)) is widely consumed as a dietary supplement to enhance bioenergetic capacity and to ameliorate the debilitative effects of the aging process or certain pathological conditions. Our main purpose in this study was to determine whether CoQ(10) intake does indeed attenuate the age-associated losses in motor, sensory, and cognitive functions or decrease the rate of mortality in mice. Mice were fed a control nonpurified diet or that diet containing 0.68 mg/g (low dosage) or 2.6 mg/g (high dosage) CoQ(10), starting at 4 mo of age, and were tested for sensory, motor, and cognitive function at 7, 15, and 25 mo of age. Amounts of the ubiquinols CoQ(9)H(2) and CoQ(10)H (2) measured in a parallel study were augmented in the cerebral cortex but not in any other region of the brain. Intake of the low-CoQ(10) diet did not affect age-associated decrements in muscle strength, balance, coordinated running, or learning/memory, whereas intake at the higher amount increased spontaneous activity, worsened the age- related losses in acuity to auditory and shock stimuli, and impaired the spatial learning/memory of old mice. The CoQ(10) diets did not affect survivorship of mice through 25 mo of age. Our results suggest that prolonged intake of CoQ(10) in low amounts has no discernable impact on cognitive and motor functions whereas intake at higher amounts exacerbates cognitive and sensory impairments encountered in old mice. These findings do not support the notion that CoQ(10) is a fitness-enhancing or an “antiaging” substance under normal physiological conditions.

Viz:

Long-term melatonin administration protects brain mitochondria from aging

J Pineal Res. 2009 Jul 1.

We tested whether chronic melatonin administration in the drinking water would reduce the brain mitochondrial impairment that accompanies aging. Brain mitochondria from male and female senescent prone (SAMP8) mice at 5 and 10 months of age were studied. Mitochondrial oxidative stress was determined by measuring the levels of lipid peroxidation and nitrite, glutathione/glutathione disulfide ratio, and glutathione peroxidase and glutathione reductase activities. Electron transport chain activity and oxidative phosphorylation capability of mitochondria were also determined by measuring the activity of the respiratory chain complexes and the ATP content. The results support a significant age-dependent mitochondrial dysfunction with a diminished efficiency of the electron transport chain and reduced ATP production, accompanied by an increased oxidative/nitrosative stress. Melatonin administration between 1 and 10 months of age completely prevented the mitochondrial impairment, maintaining or even increasing ATP production. There were no major age-dependent differences between males in females, although female mice seemed to be somewhat more sensitive to melatonin treatment than males. Thus, melatonin administration as a single therapy maintained fully functioning brain mitochondria during aging, a finding with important consequences in the pathophysiology of brain aging.

Authors: Carretero M, Escames G, López LC, Venegas C, Dayoub JC, García L, Acuña-Castroviejo D. Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada and RETICEF, Granada, Spain.

Scientists from Texas are batty over a new discovery which could lead to the single most important medical breakthrough in human history—significantly longer lifespans. The discovery, featured on the cover of the July 2009 print issue of The FASEB Journal, shows that proper protein folding over time in long-lived bats explains why they live significantly longer than other mammals of comparable size, such as mice.

“Ultimately we are trying to discover what underlying mechanisms allow for some animal species to live a very long time with the hope that we might be able to develop therapies that allow people to age more slowly,” said Asish Chaudhuri, Professor of Biochemistry, VA Medical Center, San Antonio, Texas and the senior researcher involved in the work.

Asish and colleagues made their discovery by extracting proteins from the livers of two long-lived bat species (Tadarida brasiliensis and Myotis velifer) and young adult mice and exposed them to chemicals known to cause protein misfolding. After examining the proteins, the scientists found that the bat proteins exhibited less damage than those of the mice, indicating that bats have a mechanism for maintaining proper structure under extreme stress.

“Maybe Juan Ponce De León wasn’t too far off the mark when he searched Florida for the Fountain of Youth,” said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “As it turns out, one of these bat species lives out its long life in Florida. Since bats are rodents with wings, this chemical clue as to why bats beat out mice in the aging game should point scientists to the source of this elusive fountain.”

(Journal reference: Salmon et al. The long lifespan of two bat species is correlated with resistance to protein oxidation and enhanced protein homeostasis. The FASEB Journal, 2009; 23 (7): 2317 DOI: 10.1096/fj.08-122523)

The article: Climbing the ladder to longevity: critical enzyme pair identified

Topical application of chemotherapy drug may improve appearance of aging skin

Topical application of the chemotherapy medication fluorouracil appears to reduce potentially precancerous skin patches and improve the appearance of sun-damaged skin, according to a report in the June issue of Archives of Dermatology, one of the JAMA/Archives journals.

Fluorouracil stops the body from synthesizing thymine, a building block of DNA, according to background information in the article. This drug is used to treat cancers of the colon, head and neck, pancreas and other organs. In early studies of patients with cancer undergoing treatment with systemic fluorouracil, clinicians noticed changes in skin appearance, which led to the development of a topical therapy for the treatment of actinic keratoses (skin lesions that may develop into skin cancer).

Dana L. Sachs, M.D., of the University of Michigan Medical School, Ann Arbor, and colleagues evaluated molecular and clinical changes in the skin of 21 healthy volunteers with actinic keratoses and sun-damaged skin. Participants applied 5 percent fluorouracil cream to the face twice daily for two weeks; skin biopsies and clinical evaluations were performed at the beginning of the study and periodically throughout treatment. Photographs were also taken at the beginning of the study and after one, two, four, six, 10 and 24 weeks, and were evaluated by three dermatologists who were not involved in examining the patients during the study. Nineteen patients completed all aspects of the study, and 20 responded to a questionnaire at week 10.

The number of actinic keratoses was significantly reduced following treatment, from an average of 11.6 lesions to an average of 1.5. Clinical evaluations also identified overall improvements in aging-related damage, including decreases in fine (small) and course (large) wrinkling, lentigines (dark skin spots), hyperpigmentation (skin that has become darker) and sallowness (a yellow skin tone).

One day after the final fluorouracil treatment, testing of the skin biopsies revealed an increase in the levels of compounds related to skin injury, inflammation and degradation of the extracellular matrix (the non-living tissue that supports skin), in addition to the precursor of collagen, which rebuilds damaged skin. “Topical fluorouracil causes epidermal [outer skin layer] injury, which stimulates wound healing and dermal remodeling resulting in improved appearance,” the authors write. “The mechanism of topical fluorouracil in photo-aged skin follows a predictable wound healing pattern of events reminiscent of that seen with laser treatment of photo-aging.”

The treatment was generally well tolerated. On the 10-week questionnaire, most patients rated their skin as improved (19, or 95 percent) and were willing to undergo the therapy again (17, or 89 percent).

“For patients in whom a course of topical fluorouracil is indicated for the treatment of actinic keratoses, there will likely be the additional benefit of a restorative effect from sun damage; this may provide further motivation for these patients to undergo the rigorous treatment,” the authors conclude. “It is possible that for some patients topical fluorouracil may have an important role against photo-aging. For others, however, it may not be cosmetically acceptable given that a standard course of therapy may last two to three weeks and the ensuing reaction can persist for several more weeks. Undoubtedly, there will be patients who desire a therapy such as topical fluorouracil for cosmetic purposes given the relatively low cost of this therapy compared with ablative laser resurfacing.”

(Arch Dermatol. 2009;145[6]:659-666. Available pre-embargo to the media at www.jamamedia.org.)

Wistar Institute team finds key target of aging regulator

Researchers at The Wistar Institute have defined a key target of an evolutionarily conserved protein that regulates the process of aging. The study, published June 11 in Nature, provides fundamental knowledge about key mechanisms of aging that could point toward new anti-aging strategies and cancer therapies.

Scientists have long known that a class of proteins called sirtuins promotes fitness and longevity in most organisms ranging from single-celled yeast to mammals. At the cellular level, sirtuins protect genome integrity, enhance resistance to adverse stresses, and antagonize senescence. However, the underlying molecular mechanisms have remained poorly understood. The team, led by senior author Shelley Berger, Ph.D., Hilary Koprowski Professor at The Wistar Institute, demonstrated for the first time a molecular target for a member of this class, Sir2, in regulation of aging in yeast cells. Sir2 removes an acetyl group attached to a specific site (lysine at position 16 or K16) on histone H4—histones are proteins that package and organize the long strands of DNA within the nucleus and also are central regulators in turning genes on and off. The study reveals that removal of this acetyl group by Sir2 near the chromosome ends—the telomeres—is important for yeast cells to maintain the ability to replicate. Researchers found that Sir2 levels decline as cells age, and there is a concomitant accumulation of the acetylation mark along with disrupted histone organization at telomeres.

Deacetylation of H4K16 by Sir2 and consequent telomere stability play a major role in maintaining long lifespan in yeast. Since sirtuins deacetylate many different proteins, these results clarify a key role of Sir2 protein in control of lifespan.

“Some modifications on histones, like this acetylation on histone H4 lysine 16, are persistent and are maintained through generations of cell divisions. This DNA-independent inheritance is called epigenetics,” Berger says. “Characteristic epigenetic features have been discovered for various developmental processes in recent years. Understanding epigenetic changes associated with aging is a hugely exciting direction in aging research. It will provide insights and ideas not only for new therapies to regulate cells that have lost control of proliferation, such as ‘immortal’ cells found in cancers, but also for new strategies to maintain health and fitness.”

“We plan to continue to search for new targets of Sir2 and other aging regulators,” says lead author Weiwei Dang, Ph.D., a postdoctoral scientist working with Berger. “We are designing unbiased screens for other aging targets and mechanisms in chromatin. Using yeast as our aging model enables us to do many discovery screens that are impossible with other, more complex organisms. Yet it is remarkable that many of these chromatin mechanisms associated with yeast could turn out to be relevant even for aging human cells.”

Think memory worsens with age? Then yours probably will…

Thinking your memory will get worse as you get older may actually be a self-fulfilling prophecy. Researchers at North Carolina State University have found that senior citizens who think older people should perform poorly on tests of memory actually score much worse than seniors who do not buy in to negative stereotypes about aging and memory loss.

In a study published earlier this month, psychology professor Dr. Tom Hess and a team of researchers from NC State show that older adults’ ability to remember suffers when negative stereotypes are “activated” in a given situation. “For example, older adults will perform more poorly on a memory test if they are told that older folks do poorly on that particular type of memory test,” Hess says. Memory also suffers if senior citizens believe they are being “stigmatized,” meaning that others are looking down on them because of their age.

“Such situations may be a part of older adults’ everyday experience,” Hess says, “such as being concerned about what others think of them at work having a negative effect on their performance – and thus potentially reinforcing the negative stereotypes.” However, Hess adds, “The positive flip side of this is that those who do not feel stigmatized, or those in situations where more positive views of aging are activated, exhibit significantly higher levels of memory performance.” In other words, if you are confident that aging will not ravage your memory, you are more likely to perform well on memory-related tasks.

The study also found a couple of factors that influenced the extent to which negative stereotypes influence older adults. For example, the researchers found that adults between the ages of 60 and 70 suffered more when these negative stereotypes were activated than seniors who were between the ages of 71 and 82. However, the 71-82 age group performed worse when they felt stigmatized.

Finally, the study found that negative effects were strongest for those older adults with the highest levels of education. “We interpret this as being consistent with the idea that those who value their ability to remember things most are the most likely to be sensitive to the negative implications of stereotypes, and thus are most likely to exhibit the problems associated with the stereotype.”

“The take-home message,” Hess says, “is that social factors may have a negative effect on older adults’ memory performance.”

Hess is the lead author on the study, “Moderators of and Mechanisms Underlying Stereotype Threat Effects on Older Adults’ Memory Performance.” Co-authors on the study are former NC State students Joey T. Hinson and Elizabeth A. Hodges. The study was published online April 1 by Experimental Aging Research.

A biochemical pathway that helps keep cells alive when oxygen is low also plays a role in longevity and resistance against some diseases of old age, according to a report to be published April 16 in the journal Science.
A cell’s protective reaction to a drop in oxygen is called the hypoxic response. Researchers at the University of Washington (UW) have found that nematode worms live longer if their genetic make-up permits their cells to turn on the hypoxic response under normal oxygen conditions.
Not only do these worms live longer, the researchers noted, their cells are relatively free from the toxic proteins that accumulate and clump together as an animal ages.
Dr. Matt Kaeberlein, UW assistant professor of pathology and the senior author on the study, said that defining cellular mechanisms that prevent accumulation of these proteins may point to new therapeutic targets for devastating diseases that often accompany old age in people. Toxic protein aggregations, he explained, are seen in the brain cells of those with Alzheimer’s disease, Huntington’s disease, and several other degenerative conditions that afflict the elderly.
The co-lead authors, Dr. Ranjana Mehta and Dr. Katy Steinkraus, uncovered the life-extending role of the hypoxic response while studying the mechanism by which dietary restriction slows aging in nematodes. Dietary restriction has been shown to increase life span in many different organisms, including worms, flies and mice. Kaeberlein’s group had previously found that dietary restriction also protects against toxic protein aggregation in nematode models of Huntington’s and Alzheimer’s diseases. To their surprise, however, genetic experiments mapped the hypoxic response to a previously unknown longevity pathway, different from dietary restriction.
“The research findings suggest that the hypoxic response promotes longevity and reduces the accumulation of toxic proteins by a mechanism that is distinct from both dietary restriction and insulin-like signaling. It appears to be an alternative pathway,” Kaeberlein said. “However, we don’t know if future studies might reveal that all of these different genetic pathways converge somewhere down the line into a common mechanism for delaying the effects of age.”
The key factor that controls the hypoxic response is called HIF. HIF is regulated by another protein called VHL-1, which tags HIF to be destroyed by a cellular machine called the proteasome. Destruction of HIF by VHL-1 keeps the hypoxic response “off” when oxygen is present. The UW researchers bred worms that could not produce VHL-1, leading to persistence of HIF even in the presence of high oxygen levels. They found that these worms, which were able to turn on the hypoxic response under normal oxygen conditions, lived about 30 percent longer than worms whose cells made VHL-1.
They also found that animals lacking VHL-1 were resistant to the toxic proteins known to cause Alzheimer’s and Huntington’s diseases, and that their cells accumulated less of an age-pigment called lipofuscin. Lipofuscin is thought to be one indicator of an animal’s health during aging. According to Kaeberlein, “These observations may suggest that the hypoxic response not only increases life span, but also lengthens health span and protects against the molecular processes that lead to neurodegenerative diseases in people.” Health span refers to the period of an organism’s life that is relatively free of disease.
The authors note that the hypoxic response, including HIF and VHL-1, is very well conserved in organisms from nematodes to humans, raising the possibility that modulating HIF activity may be useful for treating some age-associated diseases, and perhaps even slowing aging, in people. Kaeberlein cautions, however, that “mutation of VHL-1 is associated with a variety of tumors, and any therapies targeted toward activation of HIF would most likely need to be specific for cells that are not rapidly dividing, such as brain cells or muscle cells.”
“What we’re focused on now,” says Mehta, “is figuring out how HIF is protecting the animals from aging.” In both worms and people, HIF regulates the activity of several factors involved in growth and resistance to stress. “One or more of these factors must be the key.”
Kaeberlein agrees. “This is a completely new pathway for aging and age-associated disease. If we can understand at a very detailed level how HIF is slowing aging, we may be able to use that information to develop effective therapies for treating age-associated diseases in people.”

Press release follows:

Buck scientists identify a key protein that may explain the anti-aging and anti-cancer benefits of dietary restriction

Novato, CA, May 21, 2009. A protein that plays a key role in tumor formation, oxygen metabolism and inflammation is involved in a pathway that extends lifespan by dietary restriction. The finding, which appears in the May 22, 2009 edition of the on-line journal PLoS Genetics, provides a new understanding of how dietary restriction contributes to longevity and cancer prevention and gives scientists new targets for developing and testing drugs that could extend the healthy years of life.

The protein is HIF-1 (hypoxia-inducible factor 1). It helps cells survive by turning on when oxygen levels are low. HIF-1 is also active in some forms of human cancer. HIF-1 overexpression is frequently detected in solid tumors; inhibition of HIF-1 has been proved to be an efficient way to prevent cancer growth. Now, scientists at the Buck Institute for Age Research have shown that HIF-1 is also a key player in dietary restriction. HIF-1 is involved in a molecular pathway known to regulate cell growth and metabolism in response to nutrients and growth factors.

Previous studies on HIF-1 have mainly focused on its roles in oxygen metabolism and tumor development, said Buck faculty member Pankaj Kapahi, PhD, lead author of the study. Kapahi says the study encourages the investigation of HIF-1 in nutrient sensing pathways. The data in this study also points to HIF-1 as a likely target for regulating the protective effects of dietary restriction in mammals, said Kapahi. Dietary restriction is one of the most robust methods for extending lifespan and delaying age-related disease among various species.

Kapahi says the molecular mechanisms involved in how dietary restriction slows cancer and extends lifespan have been largely unknown. This study gets us closer to understanding that process and gives us better targets for both designing and testing drugs which could mimic the effects of dietary restriction in humans, said Kapahi.

The research involved nematode worms that were genetically altered to both under and over-express HIF-1. The animals, which are the most-often used model to study aging, were fed different diets. Animals that were designed to over-express HIF-1 did not get the benefit of lifespan extension even though their diets were restricted. Animals that under-expressed HIF-1 lived longer, even when they had a nutrient-rich diet. Furthermore, it was found that the lifespan extension resulting from dietary restriction required activity in signaling pathways in the endoplasmic reticulum, the part of the cell involved in processing and the proper folding of proteins. This finding supports the theory that aging stems from the effects of misfolded proteins and opens up a rich area of investigation to examine the mechanisms by which stress in the endoplasmic reticulum affects lifespan.

Contributors to this work:
Other Buck Institute researchers involved in the study include Di Chen, and Emma Lynn Thomas. The work was supported by the Ellison Medical Foundation, the Larry L. Hillblom Foundation, the American Federation for Aging Research, the Bill and Rita Haynes Foundation, and the National Institute on Aging.

About the Buck Institute:
The Buck Institute is the only freestanding institute in the United States that is devoted solely to basic research on aging and age-associated disease. The Institute is an independent nonprofit organization dedicated to extending the healthspan, the healthy years of each individuals life. The National Institute of Aging designated the Buck a Nathan Shock Center of Excellence in the Basic Biology of Aging, one of just five centers in the country. Buck Institute scientists work in an innovative, interdisciplinary setting to understand the mechanisms of aging and to discover new ways of detecting, preventing and treating conditions such as Alzheimers and Parkinsons disease, cancer and stroke. Collaborative research at the Institute is supported by new developments in genomics, proteomics and bioinformatics technology.

For the duration of the experiment, I consumed approximately 25mg doxycycline in the morning on top of my usual stack of supplements. Unfortunately, due to laziness and lack of time, I don’t have any objective observational data of the effects (i.e., comparative photos taken under identical conditions), so I’ll instead talk about how things appeared. I wouldn’t normally be satisfied with such subjective measurement, but the outcome was so resoundingly bad that I don’t think it matters! :/

Initially, I was perplexed that an ulcer I developed in my mouth was seeming to take far longer than normal to heal; however, this may have something to do with my expectation that healing, especially of oral wounds, would be accelerated.

The one important factor that I intended to measure was if doxycycline supplementation would do anything to increase the production of collagen in the skin. As someone who has experienced the obvious and profound (and positive) effect of oral retinoids on skin texture and quality, I was somewhat disappointed in doxycycline’s effect. Not only was there no (subjective) reduction in the number, severity, or depth of the photo-aging induced wrinkles on my face, but the doxycycline appeared to be making the condition worse!

About two weeks into the experimental period, I was continually dismayed every time I looked into the mirror at what appeared to be a ‘thinning’ of the skin on my face, particularly noticeable on my forehead, as well as more noticeable wrinkles and an overall reduction in any remnants of the youthful glow that Father Time has yet to wrestle from me. Even within the short duration of the experiment, the skin on my face started to take on that ‘papery’ stiffness one associates with the skin of the elderly.

It really was difficult to persist with the regimen in the face of what I felt to be outright failure of my idea, but I did anyway.

About ten days after ceasing the medication, I already feel my skin has mostly regained its normal texture, but I can’t be sure because I didn’t carry out any real quantitative analysis. It has definitely reverted to its normal elasticity.

All in all, I recommend not employing doxycycline to improve the quality of one’s skin. As for why this happened, I can only speculate. If we assume that doxycycline does in fact inhibit the breakdown of collagen, I suppose it could have caused a ’stiffening’ of the skin, which then caused it to appear more wrinkly and deeply lined. The perceived reduction in facial subcutaneous fat my have just been my interpretation of the changed texture. Perhaps it skews the ratio of collagen to elastin, again resulting in a reduced elasticity of the skin.

Regardless, I seem to have discovered for myself why there is apparently no research taking place regarding doxycycline as a potential ‘cosmaceutical’!