Scott Brady speaks at the Chicago Biomedical Consortium symposium, Oct. 29, 2010. (photo courtesy of the CBC)

Proteins are a little like laundry: folding matters. When folded properly, proteins can go about their intended business as the machinery of the cell, responsible for its structure and function. A misfolded protein or two can be an annoyance, temporarily throwing off the order of the cell but easily handled by a cell’s internal janitors. But when those misfolded proteins pile up like rumpled clothes across a messy room, the whole system can collapse, leading the cell to an early demise.

These catastrophic failures of folding may be the cause of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and Lou Gehrig’s Disease (amyotrophic lateral sclerosis). When pathologists look at the brains of people who die from these conditions, they find unusual changes, with missing neurons and/or abnormal deposits known by names like plaques, tangles, and Lewy bodies. As imaging techniques have improved, scientists have traced these abnormalities back to protein misfolding, with the accumulated defects leading to intracellular traffic jams and even cell suicide.

Experts in the protein folding field met October 29th at the University of Chicago as part of a special symposium organized by the Chicago Biomedical Consortium, a partnership between Chicago-area research institutions. A succession of experts talked about the intricate origami of folding polypeptide structures into functional proteins, the cellular mechanisms that help regulate that process, and the consequences when those mechanisms fail and misfolded proteins are allowed to aggregate into dangerous clumps.

“The ability of polypeptide chains in vivo to fold correctly into their native states with sufficient frequency for them to be able to execute their functions in a living organism is one of the most fundamental and remarkable phenomenons in biology,” said Sangram Sisodia, professor of neurosciences at the University of Chicago. “Despite these regulatory systems, protein misfolding and aggregation do occur, particularly as organisms age, and cause devastating diseases.”

Scott Brady of the University of Illinois at Chicago illustrated those diseases with the famous people they are associated with: Muhammad Ali and Parkinson’s disease, for example, or Woody Guthrie and Huntington’s. Brady then outlined the reasons why a pile of misfolded proteins can be so troublesome to neurons - many of which are long, skinny structures (as long as a meter in humans) that must transport proteins from one end to the other. Should an aggregate of erroneous proteins occur anywhere along that long stretch, it could cause a traffic jam fatal to the cell. Brady’s laboratory has repeatedly demonstrated this process in what is, thanks to their long, wide axons, a favorite animal model of neurobiologists: the squid.

“You may be wondering what calamari has to do with all this,” Brady said. “No, squids do not get Alzheimer’s disease, but they react to the toxic proteins in Alzheimer’s just as well as mammalian systems.”

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Dr. William Dale talks with a patient in his geriatrics clinic (photo by Bart Harris)

Creating a new research field doesn’t happen overnight. It requires bringing together like-minded researchers willing to push out into the unknown, funding agencies willing to be convinced that the new field is worth of grant dollars, and some semblance of an overall plan so that those efforts and dollars are put to optimal use. Soldering together a new field out of two existing fields can save some of the groundwork, but also creates its own set of obstacles, as representatives from each pre-existing discipline maneuver for common ground with their colleagues from across the fence.

The very young field of geriatric oncology, the study of cancer and cancer treatments in the elderly, has already jumped some of those hurdles. Most importantly, the field has a very good reason to exist, as cancer is primarily a disease of the elderly, and the U.S. population is growing increasingly older as baby boomers reach retirement age. Clinics focused on the care of elderly patients with cancer have sprung to life, including the SOCARE Clinic at the University of Chicago Medical Center. Yet there remains a void of knowledge about how cancer forms, grows, and can potentially be cured in older patients, due to clinical trials that enroll primarily younger subjects. Filling that void - and creating a field to do so - was the focus of a two-day conference last weekend at the Hilton O’Hare, where 50 members of the newly-formed Cancer & Aging Research Group discussed the fine details of how best to proceed.

Two numbers presented by NYU’s Daniel Gardner and echoed by several others demonstrated the need for geriatric oncology research: 61 percent of new cancer cases occur in people older than 65, but only 25 percent of patients on cancer clinical trials are from that age group. What’s more, the elderly that do make it into trials of new drugs and therapies are a special breed - “Olympic athletes” that meet strict enrollment requirements designed to pick research subjects that are largely free of co-morbid health conditions beyond their cancer. That leaves physicians in the dark about how to treat less healthy elderly cancer patients, with no evidence to guide their treatment decisions.

“For the vulnerable and frail adults, there’s so little data…it’s a really big population that’s coming to the clinic right now, where almost every patient I see I don’t have the right kind of evidence for,” said Supriya Mohile from the University of Rochester, who organized the conference with Arti Hurria from City of Hope Hospital in California and William Dale, section chief of geriatrics and palliative medicine at the University of Chicago.

One central question of the conference was whether to remedy that shortage by designing clinical trials specifically for older patients or by lobbying clinical researchers to include more elderly subjects in trials. Both solutions hinge upon improving recruitment rates for elderly patients, the burden of which often falls on the researchers themselves. In a talk titled “We Have Met the Enemy, and it is Us,” University of Chicago assistant professor Blase Polite showed data from several studies showing that patients older than 65 are typically half as likely to be offered an experimental cancer treatment. When elderly patients are offered the chance to enroll in a clinical trial, they are as likely - if not more so - as those under 65 to say Yes, he found.

The gap in enrolling elderly patients in clinical trial may stem from a larger problem of physician-patient communication, many presenters argued. Decisions about cancer treatment are certainly different for a 45-year-old vs. a 75-year-old, and a patient’s weighing of treatment side effects, quality of life, and the chance of a cure may change with age. But as Northwestern’s Linda Emanuel argued, physicians need to better understand that internal calculus for elderly patients facing the possibility of death.

“[There are] gratifications that are unique to those that are facing the end of life, through age or through cancer or through other terminal conditions,” Emanuel said. “What is that kind of wellbeing? I don’t think we know, we in the research field. We don’t have measures for it and we don’t have methods for it.”

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Loneliness is bad for your health. The work of John Cacioppo and others has proven this connection repeatedly over the last decade, finding links between loneliness and blood pressure, sleep quality, dementia, gene expression, and many other medical measures. The evidence has built to the point that loneliness could be considered a serious risk factor for poor health, joining more established factors such as obesity or smoking.

But for those risk factors, there are established treatments. These may not be easy for patients, but there are methods supported by science to help a person stop smoking or reduce their weight, thereby decreasing their risk of disease. However, the correct strategy for reducing a person’s loneliness is not so obvious. Is it simply a matter of surrounding a lonely person with people, giving them more opportunities to socialize? Do they need help developing social skills? Or does a lonely person need a sort of cognitive tune-up, a realignment to break out of the cycle of negative social thoughts and perceptions?

“If we know that loneliness is involved in health problems, the next question is what can we do to mitigate it,” Cacioppo, a professor of psychology at the University of Chicago, said.

Looking to build a better intervention for loneliness, Cacioppo teamed up with Christopher Masi, assistant professor of medicine at the University of Chicago Medical Center, for what’s called a meta-analysis, a wide review of the existing body of research on reducing loneliness. Essentially, the researchers looked at every study published between 1970 and 2009 that tested an intervention designed to directly target loneliness. The search brought in studies of all different types and sizes, and much of the work involved finding a way to boil their diverse study designs and results into numbers that would allow for comparison.

“Over the years there have been some qualitative reviews, not looking at the numbers quantitatively, but getting a gestalt for what seems to work and what doesn’t seem to work,” Masi said. “We thought that while that’s helpful, a quantitative meta-analysis would be more helpful and more reliable.”

In social science as well as medicine, not all studies are created equal. Some interventions were tried on a single group, with the amount of loneliness assessed before and after the treatment. Others compared a group receiving an intervention to a control group. But the gold standard was studies which compared randomized groups, minimizing any sample biases that could distort results.

Though there were only 20 such studies amidst the hundreds that the researchers uncovered, pooling their results yielded interesting findings. Previous qualitative meta-analyses concluded that group interventions were more effective than one-on-one interventions, but crunching the numbers revealed no difference between the two. Yet when all the studies were combined, the average effect on loneliness was significant, providing evidence that loneliness is indeed sensitive to treatment.

“We rigorously focused on the best studies and we still found a significant effect,” Masi said.

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A great deal of attention has been paid in recent years to the issue of racial and ethnic health disparities. Statistic after statistic reveals that minorities in the United States, particularly African-American and Hispanic populations, are in poorer health on average compared to American whites. Infant mortality, heart disease, diabetes, obesity, cancer and other maladies appear in often shockingly higher rates in minority populations, reflecting differences frequently attributed to socioeconomic factors and access to quality health care. But a new study by University of Chicago Medical Center researchers finds that a major contributor to those disparities might be traced back to what’s in the medicine cabinet.

The National Social Life, Health, and Aging Project (NSHAP) is a research effort launched out of the University of Chicago to study a large sample of older Americans. In 2005 and 2006, more than 3,000 in-home interviews were conducted across the country with people between the ages of 57 and 85 about their social activity, their health, and their medical care. As part of the interview, researchers not only asked the subject what medications they were currently taking, they looked at the drugs with their own eyes, taking a medication inventory “by direct observation.”

That thorough scan allowed Dima Qato, Caleb Alexander, and colleagues to analyze racial and ethnic patterns of medication use with unprecedented high fidelity. Previous studies which used insurance claims or prescriptions written to measure medication usage missed a key human factor, said Alexander, assistant professor of medicine.

“As we all know from own experience, what you are prescribed and what you take are often quite different,” Alexander said. “This data was unique in that it allowed for us to observe, from a nationally representative sample of individuals, the medicines people were actually taking.”

The analysis focused on medications prescribed to people at high risk for cardiovascular disease, a condition that has seen great progress recently in preventive medicine. Those included both the cholesterol-lowering prescription drug class of statins and the well-known over-the-counter drug aspirin, which is recommended to people at risk of heart attack and stroke for its anti-clotting abilities. Before the researchers even got to comparing different races and ethnicities, a disturbing overall trend appeared regarding use of these medicines.

“We found that across the board, regardless of race, there was evidence of under-use of both stains and aspirin,” said Qato, a research associate in the Department of Obstetrics & Gynecology.

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ED and STDs: Unfortunate Acronym Bedfellows

With the constant drumbeat of advertisements for erectile dysfunction drugs, most of us can probably recite the list of precautions and side effects by heart by now. Though some of them inspire juvenile giggling (the one about “lasting more than 4 hours,” in particular), one warning is a head-scratcher: “does not protect against sexually transmitted diseases, including HIV.” Saying so always struck me as sort of a “duh” statement, but there had to be a reason for it to be there as part of the FDA-mandated laundry list of disclaimers for pharmaceutical advertising.

Indeed, there have been some studies that suggest men using ED drugs are at higher risk for STDs, which makes sense if you consider they will presumably be having more sex. But a new study in Annals of Internal Medicine of the STD rate in older men both before and after they receive a prescription for ED medication indicates that it’s not so much the drug, but the patient. The authors, which include Amee Kamdar of the University of Chicago Booth Graduate School of Business, analyzed the insurance claims of nearly 1.5 million men older than 40, comparing the rates of diseases such as HIV, chlamydia and syphilis in those who did or did not receive a prescription for an erectile dysfunction drug.

Those who sought treatment for ED did indeed have roughly twice the STD rate of the control population. But when those numbers were broken down into the year before ED prescription and the year after, the STD rate and risk was unchanged for those who received the drugs. That finding suggests that treatment of ED is not responsible for riskier sexual behavior, but people who engage in risky sexual behavior are more likely to seek treatment for ED. “The observed associated between ED drug use and STDs may have more to do with types of patients using ED drugs rather than a direct effect of ED drug availability on STD rates,” the authors conclude.

Clinically, the paper adds further argument for improved discussion of sexual issues with older patients, a topic covered previously on the blog regarding the research of our own Stacy Tessler Lindau. Studies have found that only 9 percent of adults between the age of 40 and 80 discussed sexual health with their physician during a routine visit, and opinion pieces (one called “Time for ‘the talk’ - again”) have argued that doctors should monitor the sexual practices of aged patients as much as younger ones. As the new study shows, when patients “talk to their doctor about ED,” the doctor should talk back about STDs.

What a Fumbled Handoff Looks Like

Last week, as expected, the Accreditation Council for Graduate Medical Education recommended further restrictions on the number of hours that medical residents can work. Under the new guidelines, first-year residents will not be allowed to work for longer than 16 consecutive hours (as opposed to the occasional 30-hour shift today) and more direct supervision by older residents and attending physicians will be required. The new guidelines are not yet settled - there’s a 45-day public comment period currently underway - but there is already plenty of research into the pros and cons of further restricting a resident’s time in the hospital (we’ll have more coverage of the guidelines debate soon).

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The World Cup in South Africa has rightly given the people of the continent reason to celebrate and show off their ability to host an international party. But there remain severe political, economic, and health problems in Africa that a month-long soccer tournament can do little to repair. A primary concern is the epidemic of HIV/AIDS that has swept across African countries, reducing average life expectancy by as much as 20 years in some countries.

The face of this tragedy is often the millions of AIDS orphans left behind when their parents succumb to the disease. But depleting an entire generation of people has ripple effects in both directions, a recent study by University of Chicago and Stanford University researchers finds. Since the disease, unlike most, kills largely young and middle-age people, the other demographic left behind are the elderly. As Tim Kautz, an economics graduate student at the University of Chicago, and his colleagues found, the older generation is left with greater responsibility and less support.

The study, published last week in the British Medical Journal, used huge demographic surveys of 22 countries in sub-Saharan Africa to analyze the effects of the AIDS epidemic on the elderly. Despite the huge dip in the middle age groups, the elderly population of Africa is growing - expected to rise 55 percent between now and 2025, according to a United Nations report. In countries where it remains traditional for adult offspring to take care of their ancestors, it’s a real problem when those offspring are disappearing. Kautz observed that family structure firsthand while leading AIDS education courses in Tanzania one summer during his undergraduate years.

“What I observed while I was there living with a host family, made me realize family how the living arrangments are so different from the United States,” Kautz said. “I saw how elderly people lived with adult children…and how important informal networks and family were in caregiving. ”

As an undergraduate at Stanford, Kautz worked with the Center for Health Policy to study the effect of the AIDS epidemic on the elderly population of Africa. Analyzing the surveys, the researchers determined that the number of unattended elderly people (defined here as 60 or older) has already begun to spike, moving from 23.5 percent in 1993 to 26.1 percent in 2004. Extrapolating to the future, that rise is expected to continue; according to their calculation, every one percent increase in AIDS mortality rate leads to a 1.53 percent increase in older people living by themselves. Some more math, and an estimated 582,000 to 917,000 newly unattended elderly people were created in 2006 alone.

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No, the blog has not been hijacked by spammers.

Radio silence was necessary yesterday as a I fielded media calls for a new study in the British Medical Journal on the eyebrow-raising subject of “sexually active life expectancy.” Stacy Tessler Lindau, associate professor of obstetrics/gynecology at the University of Chicago Medical Center, and Natalia Gavrilova, senior research associate, coined the term after mining two large aging surveys for information on health and sex in the golden years. That work, as you can see in coverage at CNN, the BBC, Time, the Los Angeles Times, and AOL, struck a chord with media outlets targeting baby boomers moving into their late 50’s and 60’s.

In what may not be surprising news for a culture inundated with erectile dysfunction ads, the sex life of many seniors remains robust, the study showed. But when broken down by gender, the story gets a little more complicated. When calculated from age 30, sexual life expectancy for men is nearly 35 years, while sexual life expectancy for women is closer to 31. Those numbers are fairly close, but there’s a key denominator difference - men, on average, die younger than women, leaving women with a greater percentage of their older years in a sexually inactive state.

If you push the axis for calculating sexually active life expectancy to age 55, the difference is more striking. Once a man reaches double nickels on the odometer, they can expect on average of 15 more years of sexual activity. For women, the figure is much lower, only 10.6 years. By age 75, only 16.8 percent of women were sexually active compared to 38.9% of men. That gap may be in part due to those little-blue-pill ads; Lindau and Gavrilova observed more sexually interested men in the 57-64 age group of a survey conducted in ‘05-06 than in a survey performed 10 years earlier.

“Interest in sex, participation in sex and even the quality of sexual activity were higher for men than women, and this gender gap widened with age,” Lindau told my colleague John Easton. But the study “affirms a positive association between later-life health, sexual partnership and sexual activity.”

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