Why Muscles Weaken With Age and Points to Possible Therapy

http://www.sciencedaily.com/releases/2011/08/110802125549.htm

Sarcopenia, which begins to appear at around age 40 and accelerates after 75, is a major cause of disability in the elderly. Exercise can help counter the effects of age-related muscle loss. sarcopenia occurs when calcium leaks from a group of proteins in muscle cells called the ryanodine receptor channel complex. These leaks then trigger a chain of events that ultimately limits the ability of muscle fibers to contract, leaky ryanodine receptors are involved in the development of heart failure and arrhythmias. In 2009, he showed that leaks in these channels also contribute to Duchenne muscular dystrophy, a genetic disorder characterized by rapidly progressing muscle weakness and early death.

Dr. Marks suspected that ryanodine receptor leakage may also be involved in age-related muscle loss, which the present study shows is the case. "This is a completely new concept -- that the damage that occurs in aging is very similar to what happens in muscular dystrophy," says Dr. Marks, "thus as we age we essentially develop an acquired form of muscular dystrophy."
Both the aging process and the genetic defect responsible for muscular dystrophy cause an increase in the production of oxygen free radicals, highly reactive and harmful molecules. "Our data suggest that this sets up a vicious cycle, in which the free radicals cause ryanodine receptors to leak calcium into the cell. The calcium poisons mitochondria -- organelles that power the cell -- leading to the release of even more free radicals. This, in turn, causes more calcium leakage. With less calcium available for contraction, the muscles get weaker," says first author Daniel C. Andersson, M.D., Ph.D., a postdoctoral fellow in physiology and cellular biophysics at CUMC.
The study also points to a possible therapy for sarcopenia: an experimental drug called S107, developed by Dr. Marks and his colleagues. The drug acts by stabilizing calstabin1, a protein that binds to ryanodine receptors and prevents calcium leakage.
In the study, 24-month-old mice (roughly the equivalent of 70-year-old humans) were given S107 for four weeks. The mice showed significant improvements in both muscle force and exercise capacity, compared with untreated controls. "The mice ran farther and faster during voluntary exercise," says Dr. Andersson. "When we tested their muscles, they were about 50 percent stronger." The drug had no effect on younger mice with normal ryanodine receptors.
A similar drug is now in phase II clinical trials for the treatment of heart failure.
"Most investigators in the field of aging have been saying that the way to improve muscle strength is to build muscle mass, using such therapies as testosterone, growth hormone, and insulin-like growth factor-1," says Dr. Marks. "But an increase in muscle mass is not necessarily accompanied by an increase in muscle function. Our results suggest that you can improve muscle function by fixing leaky calcium channels. And in fact, treating aged mice with S107 enhanced muscle strength without increasing muscle size, at least during the four-week treatment period."

Restoring Happiness in People With Depression

People often underestimate the long-term impact of practicing brief, positive activities, Lyubomirsky said. For example, if a person gets 15 minutes of positive emotions from counting her blessings, she may muster the energy to attend the art class she'd long considered attending, and, while in class, might meet a friend who becomes a companion and confidant for years to come. In this way, even momentary positive feelings can build long-term social, psychological, intellectual, and physical skills and reserves.
The researchers' review of brain imaging studies also led them to theorize that PAIs may act to boost the dampened reward/pleasure circuit mechanisms and reverse apathy -- a key benefit that does not usually arise from treatment with medication alone.
"The positive activities themselves aren't really new," said Layous, the paper's lead author. "After all, humans have been counting their blessings, dreaming optimistically, writing thank you notes, and doing acts of kindness for thousands of years. What's new is the scientific rigor that researchers have applied to measuring benefits and understanding why they work."
A major benefit of positive activities is that they are simple to practice and inexpensive to deliver.
"If we're serious about tackling a problem as large as depression, we should be as concerned about the scalability of our solutions as much as their potency," Chancellor said,
While PAIs appear to be a potentially promising therapy for mild forms of depression," Doraiswamy cautioned, "they have not yet been fully studied in people with moderate to severe forms of depression. We need further studies before they can be applied to help such patients."  http://www.sciencedaily.com/releases/2011/07/110729175803.htm

Some Exercise Is Better Than None: More Is Better to Reduce Heart Disease Risk

http://www.sciencedaily.com/releases/2011/08/110801161414.htm

People who engaged in 150 minutes of moderate-intensity leisure activity had a 14 percent lower risk of coronary heart disease (CHD) compared to those who reported no exercise or physical activity. At higher levels of activity, the relative risk of CHD was progressively lower. Researchers found that even people who got below the United States guidelines for physical activity, which recommends 2 hours and 30 minutes of moderate exercise per week, had a lower risk of CHD than those who had no activity.
"The overall findings of the study corroborate federal guidelines -- even a little bit of exercise is good, but more is better -- 150 minutes of exercise per week is beneficial, 300 minutes per week will give even more benefits," said Jacob Sattelmair, ScD, of the Department of Epidemiology at the Harvard School of Public Health.

Chance Favors the Concentration of Wealth, -Estate Tax prevents, should be called Redistribution Taxes

Figure 1. Concentration of wealth over time. All simulations start with an even distribution of wealth. Unless otherwise noted, all simulations
were run with 100,000 individuals and a 5% yearly average return on investment. Red lines show the analytically expected trajectories (Eqn. 1); points
show the results from individual-based simulations. Three replicate simulations were run for each high variance simulation. (A) Higher variance
among individual rates of return increases the rate of wealth concentration. (B) Inequality as measured by the Gini coefficient also increases over
time. (C) Wealth concentrates even when the mean growth rate varies over time, such that in some years the total economy grows and in others the
economy shrinks. Average annual rates of return were randomly drawn from a normal distribution with m~ln 1:08&7:7% and s~0:19, with a new
value for the economy drawn each year. (D) Population growth and splitting estates among heirs does not significantly reduce rate of wealth
concentration. Dashed blue line shows the growing population. (E) A tax on inherited fortunes slows and arrests the concentration of wealth. (F)
Immigrants with mean wealth slow but do not arrest the concentration of wealth. Dashed blue line shows population increase from immigration.
doi:10.1371/journal.pone.0020728.g001
http://www.sciencedaily.com/releases/2011/07/110721172334.htm

Fewer Verbs and Nouns in Financial Reporting Could Predict Stock Market Bubble, Study Shows

 When the language used by financial analysts and reporters becomes increasingly similar the stock market may be overheated, say scientists.

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After examining 18,000 online articles published by the Financial Times, The New York Times, and the BBC, computer scientists have discovered that the verbs and nouns used by financial commentators converge in a 'herd-like' fashion in the lead up to a stock market bubble. Immediately afterwards, the language disperses.

"Our analysis shows that trends in the use of words by financial journalists correlate closely with changes in the leading stock indices -- the DJI, the NIKKEI-225, and FTSE-100,"
"By plotting the distributions of words used in financial articles published online between 2006 and 2010 into a computer model, we were able to identify what we call 'verb convergence' and 'noun convergence -- where the language used by financial journalists shows converging agreement."
"Our study shows that reporters converge on the same language -- 'stocks rose again', 'scaled new heights', or 'soared' -- as their commentaries became more uniformly positive in the lead up to the 2007 crash."
"They also appear to refer to a smaller-than-usual set of market events -- presumably because of an increased fixation on a small number of rapidly rising stocks,"http://www.sciencedaily.com/releases/2011/07/110718101202.htm

Novel Compound Selectively Kills Cancer Cells by Blocking Their Response to Oxidative Stress

The plant-based compound piperlongumine (PL), derived from the fruit of a pepper plant found in southern India and southeast Asia, appears to kill cancer cells by jamming the machinery that dissipates high oxidative stress and the resulting ROS. Normal cells have low levels of ROS, in tune with their more modest metabolism, so they don't need high levels of the anti-oxidant enzymes that PL stymies once they pass a certain threshold.
"Piperlongumine targets something that's not thought to be essential in normal cells," said Stuart L. Schreiber, a senior co-author and director of the Broad's Chemical Biology Program. "Cancer cells have a greater dependence on ROS biology than normal cells."
Sam W. Lee and Anna Mandinova, senior co-authors from the Cutaneous Biology Research Center (CBRC) at MGH, weren't looking for a ROS inhibitor when they found PL. Their interest lay in the tumor suppressor gene p53, which is mutated in more than half of all cancer types. Teaming up with the Broad's Chemical Biology Program and Platform to screen libraries of chemical compounds, they were looking for something that might increase levels of the properly functioning p53 gene.
When they saw a promising signal for PL, they assumed it worked by enhancing the p53 gene. But to their surprise, PL induced cancer cell death independent of the tumor suppressor gene's activity. And when they tested PL in normal cells, the cells didn't die.
"The novelty of this compound was that it was able to recognize cancer cells from normal cells," said Mandinova, a Broad associate member and a faculty member at MGH and Harvard Medical School. "It has a mode of action that targets something especially important to the cancer cell."
Their second surprise came after the Proteomics Platform's quantitative analysis identified the target of PL. The researchers imagined that they might find a protein encoded by a cancer-causing gene was being inhibited in some way, but instead of an oncogene, they saw an indirect process on which cancer cells depend.
A small number of new cancer drugs target oncogenes directly, but this may not be the only promising new direction for treating cancers. Cancer genes do not act alone. PL exploits a dependency that develops after oncogenes transform normal cells into cancer cells.
"Our studies suggest that piperlongumine's ROS-associated mechanism is especially relevant to the transformed cancer cell," said co-author Andrew M. Stern, associate director of Novel Therapeutics at the Broad. "And this in part may underlie the observed selectivity of PL."
The scientists tested PL against cancer cells and normal cells engineered to develop cancer. In mice injected with human bladder, breast, lung, or melanoma cancer cells, PL inhibited tumor growth but showed no toxicity in normal mice. In a tougher test of mice that developed breast cancer spontaneously, PL blocked both tumor growth and metastasis. In contrast, the chemotherapy drug paclitaxel (Taxol) was less effective, even at high levels.
"This compound is selectively reducing the enzyme activity involved in oxidative stress balance in cancer cells, so the ROS level can go up above the threshold for cell death," said Lee, a Broad associate member and associate director of CBRC at MGH. "We hope we can use this compound as a starting point for the development of a drug so patients can benefit."
While hopeful, the authors remain cautious. Much more work needs to be done to better understand how the ROS process differs between normal and cancer cells before clinical studies can even be launched. Further studies will focus on different forms of cancer and their genotypes, or genetic information.
"Our next set of goals is to learn if there are specific cancer genotypes that will be more sensitive to this compound than others," said Alykhan F. Shamji, associate director of the Broad's Chemical Biology Program. "We hope our experiments will help be predictive of whether patients with the same genotypes in their tumors would respond the same way. It would help us to pick the right patients."
The research reported in Nature was funded by the National Cancer Institute and builds on work performed through the Initiative for Chemical Genetics and the Cancer Target Discovery and Development Network.http://www.sciencedaily.com/releases/2011/07/110713131421.htm

Size Matters: Why Do People Eat Less When They Have Big Forks?

Learn to know what it takes to be full, instead of relying on external cues like forks:

"The fork size provided the diners with a means to observe their goal progress," the authors explain. "The physiological feedback of feeling full or the satiation signal comes with a time lag. In its absence diners focus on the visual cue of whether they are making any dent on the food on their plate to assess goal progress."

The authors tested this conclusion by varying the quantities of food. They found that when the initial quantity of food was more (a well-loaded plate) diners with small forks ate significantly more than those with large forks. When customers were served small servings, the fork size did not affect the amount of food. Interestingly, in a lab experiment the authors found that participants with small forks consumed less than those with large forks. The authors believe that the participants did not have the same goals of satiating hunger as the restaurant customers did.
To avoid overeating, the authors suggest consumers learn to better understand hunger cues. "People do not have clear internal cues about the appropriate quantity to consume," the authors write. "They allow external cues, such as fork size, to determine the amount they should consume."http://www.sciencedaily.com/releases/2011/07/110714150949.htm