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Combined Therapy Reduces Infections in the Elderly

A combination therapy may restore some strength to the aging immune system, limiting the risk of infection in older adults. | Justin/ Flickr

Across the world, infections such as influenza and pneumonia take a serious physical toll on the elderly. Now, a research team has devised a combination treatment that safely fortifies the immune system of the elderly against these infections, according to a study published in the July 11 issue of Science Translational Medicine.

The findings from the clinical trial show individuals over the age of 65 who received the therapy displayed at least a 35% drop in the rate of all infections for a year compared to a placebo group. The treatment also improved the response of the immune system to a seasonal flu vaccine, indicating it could help address a leading cause of death in elderly individuals.

As people grow old, their immune system begins to lose some of its ability to defend the body against foreign invaders. This phenomenon — called immunosenescence — leads to increased rates of infections in the elderly, especially those of the respiratory tract.

As a result, infections represent one of the leading causes of death in people over 65 years of age. The elderly are particularly vulnerable to lung infections; in 2013, an estimated 85% of all deaths from pneumonia and the flu in the U.S. occurred in those aged 65 years and older, according to a report from the American Lung Association. Infections such as urinary tract infections can also indirectly exacerbate pre-existing conditions and are a predictor of future disability.

"Improving immune function in older people is important because the function of almost every type of immune cell declines with age," said Joan Mannick, chief medical officer at resTORbio in Boston, Massachusetts and lead author of the new study. "This leads to high rates of infections and inadequate responses to vaccinations."

Research has indicated that inhibiting the activity of the TORC1 complex — a protein structure that is implicated in the aging process — extends lifespan and combats immunosenescence in rats and other animal species, according to Mannick. In a previous study, her research team found that a drug named everolimus (currently approved for use in organ transplants) that inhibits TORC1 increased the production of antibodies against the flu virus in elderly volunteers who received a flu vaccine, indicating they responded to the vaccine in a more effective manner.

Excited by their initial results, Mannick's group continued to examine the beneficial effects of inhibiting TORC1 on vaccine responses. They also decided to investigate whether inhibitors could reduce the risk of infections over an extended time period in a phase 2a clinical trial — a study designed to demonstrate that a drug candidate works as intended.

Respiratory tract infections are a significant health risk in older populations.| resTORbio

The study authors recruited 264 volunteers over the age of 65 who had no serious medical conditions, and randomly split the subjects into four different groups. Three groups received different doses of either everolimus or another TORC1 inhibitor named BEZ235 for six weeks, and a fourth group received low doses of both compounds.

One year after treatment began, all four treated groups had a lower rate of all infections compared to a group that received a placebo. The group that received both TORC1 inhibitors displayed the lowest average infection rate (1.49 infections per person) compared to the placebo group (2.41 infections per person).

People in the four treatment groups did not display any more severe health events compared to those in the placebo group. However, they did experience a higher rate of certain mild side effects such as diarrhea.

Similar to their previous study, Mannick and colleagues also found that the treated groups had increased antibody production and an improved immune response towards a seasonal flu vaccine that was administered two weeks after treatment ceased.

How exactly TORC1 inhibition strengthens the immune system remains unclear. Mannick noted the improvement in flu vaccine response does not explain the lower rate of respiratory tract infections. The decrease, she says, is instead partly due to an uptick in the activity of antiviral genes that the authors observed in the treated groups.

"Given that the great majority of respiratory infections are caused by common cold virus infections for which we have no treatment, these findings are clinically important," said Sebastian Johnston, professor of respiratory medicine and allergy at Imperial College London, United Kingdom. Johnston is a paid consultant for resTORbio, but is not affiliated with the new study.

However, Johnston cautioned that the study only enrolled roughly 50 subjects per treatment group, adding that further work should extend these findings into larger numbers of elderly individuals before a clinical application can be developed. Researchers should also investigate whether TORC1 inhibition could alleviate chronic respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD), he said.

Mannick's group is completing a phase 2b clinical trial to determine the optimal doses of TORC1 inhibitors for improving immune function. From that point, the scientists plan to conduct additional clinical trials to assess the impact of TORC1 inhibitors on other aging-related conditions.