Research conducted in the Howlett lab has three major objectives:
To determine how long-term exposure to low levels of听circulating testosterone affects the heart and whether testosterone听therapy is harmful or beneficial in the setting of aging.
To explore the links between estrogen, aging and heart disease.
To investigate how frailty affects the heart鈥檚 ability to function under normal conditions and during times when blood flow to the听heart is reduced.听听
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1. Testosterone 听听
Heart disease increases with age in men and women as sex hormone levels fall.听 Since a women鈥檚 risk of heart disease goes up after menopause, there has been a lot of interest in the idea that estrogen influences heart disease.听 However, it is now clear that testosterone decreases with age not only during 鈥渕anopause鈥� in men, but in women too.听 Marketing campaigns focused on testosterone鈥檚 benefits have increased the use of testosterone supplements in older people.听 Our goal is to explore effects of low testosterone and testosterone supplementation on the heart.听
Key findings/planned experiments
We have discovered that age decreases the ability of male hearts to contract by changing the ability of heart cells to regulate internal calcium.
We showed that low testosterone upsets the ability of heart cells to contract and regulate intracellular calcium, which may lead to diseases like heart failure.
We will follow middle aged mice (1 year old) and follow them until they reach 2 years of age, which is about 85 human years, and see how long term exposure to low testosterone changes the ability of the heart to contraction.
We will also treat male and female mice with testosterone to find out if testosterone therapy is beneficial or harmful and if this depends on the dose used.
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2. Estrogen
Pre-menopausal women are less likely to suffer from heart disease than are men, but this advantage disappears with age.听 This suggests that sex hormones such as estrogen influence heart disease.听 Even so, we know very little about the effects of estrogen on the heart, in part because most laboratory studies still use only male animals.听 Our group is investigating the effects of estrogen on heart function.
Key findings/planned experiments
We discovered that calcium levels inside individual heart cells are lower in cells from young adult females compared to males.
To mimic menopausal changes we removed the ovaries from some female mice, which caused the calcium levels in their heart cells to rise dramatically.
We saw a similar increase in calcium levels in cells from very old female mice.
We will investigate the mechanisms by which estrogen influences calcium regulation in heart cells.
We will treat young and old animals with a new drug called G-1 (mimics the beneficial effects of estrogen) to find out whether G-1 can improve heart function under disease conditions.
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3. Frailty
As anyone who has ever attended their high school reunion knows, people age at different rates.听 Because a person's actual age is not always the same as their biological age, some older adults are fit and others are frail.听听 Frailty is a major health care problem, because frail people are often harmed by traditional medical care.听 Even so, we know very little about frailty and its effects on organs like the heart, in part because we have not had an animal model to investigate frailty and its potential treatment.听 The goal of our research is to understand how frailty affects the heart鈥檚 ability to function under normal and diseased conditions.
Key findings/planned experiments
We have discovered how to measure frailty in aging mice with a tool called a frailty index, which counts different health problems in individual mice.
We found that individual heart cells become very large in frail animals, the ability of these large cells to contract declines, which reduces the force of the heartbeat.
Our work is looking at how frailty develops over time in mice and comparing our results to what is known about frailty in people.
We are also treating older mice with drugs that may help treat frailty and we will explore how this treatment works.
