Elder Pharmacology

Studying and treating the chronic diseases
associated with aging needs serious revamping.
BY NIR BARZILAI

What is the greatest menace associated with age-related
diseases? Hypertension? Obesity? High cholesterol?
No. It’s simply the number of years an individual lives.
For example, elevated plasma cholesterol is considered a major
risk factor for cardiovascular-disease death. Yet, when compared
with aging itself, the risk of high cholesterol alone pales. For a typical
adult, high cholesterol poses a threefold increase in the risk of
dying from cardiovascular disease. Simply aging from 35 to 85,
however, increases that risk about a thousand fold.
Similar patterns are observed for cancer, type 2 diabetes,
and Alzheimer’s disease. National Institutes of Health data
indicate that the risk of dying from these diseases accelerates
logarithmically by approximately 100 to 1,000-fold between
ages 35 and 85. No wonder so many elderly people deal with
several age-related diseases simultaneously, and can face
additional complications from taking multiple drugs, prescribed
separately to treat each disease.
This reality is further aggravated by the fact that many carefully
conducted clinical trials exclude patients over the age of 65
as well as patients taking multiple drugs. This means that while
the majority of drugs are consumed by the elderly, there is little
to no “evidence-based medicine” to inform us about the safety
of polypharmacological therapy for this population.
And an even more fundamental problem looms.
Gerontologists have made significant progress in understanding
the biology of aging. They’ve identified pathways
involved in normal aging, flagged genes associated with
increased longevity, and even extended healthy life span by
genetic means, nutritional manipulation, or through drugs in
a variety of animal models, including mammals.
One conclusion from these studies is that the biology of a
young body is substantially different from that of an old body.
Not every treatment that works in the young will work or be
safe in the elderly.
Estrogen therapy for postmenopausal women exemplifies
this. The Women’s Health Initiative terminated its landmark
study on estrogen replacement because study participants were
showing higher-than-expected levels of breast cancer, cardiovascular
disease, and cognitive decline. In retrospect, many mechanistic
studies on rodents have used young, ovariectomized female
mice as models to induce cardiovascular disease, stroke, or other
diseases relevant to human females. In that research, estrogen
seemed protective. However, when those studies were repeated
in older, postmenopausal female mouse models, estrogen therapy
was detrimental. The fact that a single drug like estrogen did not
show anti-aging properties or protections opens the possibility
that this holds true for many other approved drugs used to treat
chronic conditions associated with aging.
The increased use of statins to treat cardiovascular disease—
one of the biggest contributions to mortality in the
Western world (~40 percent)—is another example. There is
no doubt that statins have decreased the occurrence of cardiovascular
events and mortality. And recent recommendations
have emerged that may lead to even more people being
treated with this drug class.
However, statins consistently did not change overall mortality!
How does this math work? If statins reduce a major
cause of mortality, but do not change overall mortality, it suggests
people on statins die from other causes. Indeed, we and
other researchers have shown that statin use significantly
increases diabetes risk, supporting the notion that these
drugs may actually contribute to other diseases of aging (Diabetes
Care, 32:1924-29, 2009).
In the statin case, it is important to note who is pushing the
agenda. Because of great progress in preventing and treating
cardiovascular disease, cardiologists have deepened the belief
that heart health is central. Cardiologists also inform us that
decreased blood pressure is good for the heart. But studies have
shown that blood pressure status and cognitive function in the
elderly are related. Low blood pressure in elderly people is associated
with reduced cognitive performance, while mild hypertension
may help prevent cognitive decline (Am J Hypertens,
16:818-26, 2003). Other studies have suggested that treating
high blood pressure with some drugs may accelerate cognitive
decline (Amer J Ther, 17:358-64, 2010).
So, if there are real risks associated not just with multiple
drugs but with any single drug, what solutions must we consider?
First, in order to ensure safety and effectiveness, a significant
percentage of elderly subjects (at least 50 percent of the study sample)
needs to be included in clinical drug trials for any age-related
disease. Another approach is to design a sub-trial on the elderly.
Second, when a drug is promoted by a medical professional
group, its effect on overall mortality needs to be assessed. It
has to be clear that this drug is not merely exchanging one disease
for another.
Third, studies of exceptionally long-lived people, such as the
LonGenity and Longevity Genes Project at Albert Einstein College
of Medicine, which includes healthy centenarians and their
families, have identified functional genetic changes associated with
such longevity. The goal of such research is to translate these findings
into drugs that can extend healthy life span for people who do
not share this genetic pattern, and some drugs based such projects
are currently in clinical trials.
Lastly, and most important, developing drugs that are based
on an understanding of the biology of aging has the potential to
provide therapies for the prevention of many age-related diseases.
Such a strategy may promote healthy life spans and significantly
reduce the financial burden of late-life illness and
end-of-life care.
Nir Barzilai is a professor of medicine and genetics at Albert
Einstein College of Medicine of Yeshiva University in New York
City and director of Einstein’s Institute for Aging Research and
its two Centers of Excellence (NIH-Nathan Shock Center and
Paul F. Glenn Center for the Biology of Human Aging Research).
He is also the co-scientific director of the American Federation
for Aging Research. His research focuses on mechanisms of
aging, including the genetic determinants of life span and the
role of nutrients in extending life.

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