Kavazis, Hood research sheds new light on female reproduction and lactation

July 18, 2018

Pictured from left to right are sophomore Chemistry and Biochemistry major Ryleigh Randall, Biological Sciences post-doc Kristjan Niitepõld (Ph.D.), Kinesiology doctoral student Hailey Parry, Andreas Kavazis (Ph.D.), Associate Professor in the School of Kinesiology in the College of Education, and Wendy Hood (Ph.D.), Associate Professor in Biological Sciences.
Pictured from left to right are sophomore Chemistry and Biochemistry major Ryleigh Randall, Biological Sciences post-doc Kristjan Niitepõld (Ph.D.), Kinesiology doctoral student Hailey Parry, Andreas Kavazis (Ph.D.), Associate Professor in the School of Kinesiology in the College of Education, and Wendy Hood (Ph.D.), Associate Professor in Biological Sciences.

For a long and healthy life, women should exercise, have two to four kids, and breastfeed them. Well, it may be a little more complicated than that, but research performed by Wendy Hood (Ph.D.), Associate Professor in Biological Sciences, and Andreas Kavazis (Ph.D.), Associate Professor in the School of Kinesiology in the College of Education, clearly shows three things: 1) exercise has a beneficial effect on reproduction; 2) lactation after parturition (i.e., giving birth) lowers the risk of metabolic diseases; and 3) reproduction can increase longevity (i.e., lifespan).

Hood is an evolutionary biologist whose research focuses on reproductive performance and life history tradeoffs, offspring performance, and the impact of lactation on human health. Kavazis’s expertise is in mitochondrial function and bioenergetics, particularly the physiological adaptations that occur in different tissues during various metabolic loads such as exercise, reproduction, and lactation. The researchers have secured a $150,000 National Institutes of Health (NIH) grant (RO3) and two National Science Foundation (NSF) grants. One is $1 million for five years (a Career Award to Hood as the Primary Investigator and Kavazis as a Co-PI). The other is $4 million for four years, $1.5 million of which is awarded to Auburn (an EPSCoR Grant to Hood, Kavazis, and a biomedical scientist at the University of South Carolina as co-PIs).

Historically, scientists assumed that every reproductive event had a negative effect on the body. Reproduction, which necessitates large energy expenditure, increases reactive oxygen species (ROS) production. ROS are produced when electrons escape from the electron transport chain during mitochondrial respiration, the process that creates most of the energy in our cells. Increased ROS production can lead to oxidative damage in the mother’s body, damaging her proteins, lipids, and DNA, ultimately shortening her lifespan.

Or so we thought.

This assumption is now being challenged by the research of Hood and Kavazis whose findings indicate that a moderate level of oxidative stress from reproduction is potentially beneficial, rather than harmful, to the body.

For a century, scientists have realized that more reproductive events cause a shorter lifespan. This concept has been observed both within and across species. For example, mice have multiple offspring at a time; the time between gestation periods is relatively short, and mice tend to have a shorter life. On the contrary, deer have only one offspring at a time, have fewer reproductive events during their lifespan, and tend to live a longer life. Hence, scientists assumed that the relationship between reproduction and longevity was inversely proportional. In actuality, the relationship may be more of a parabola, thanks to the emerging theory of “mitochondrial hormesis” being investigated by the Auburn scientists.

Mitochondrial hormesis, or mitohormesis, is the term given to the concept that increased formation of ROS within the mitochondria may cause an adaptive reaction, which produces increased stress resistance and a long-term reduction of oxidative stress. The term “hormesis” actually comes from the toxicology literature referring to a biphasic dose response to an environmental agent. For example, a low dose stimulation leads to a beneficial effect and a high dose stimulation leads to an inhibitory or toxic effect. Exercise has a hormetic effect, because at moderate levels it is healthy. However, at very high levels it can be damaging. The literature on the number of children and mortality also indicates that a low number of offspring, namely two to four, is not damaging metabolically.

“I now put reproduction in an exercise context,” said Hood. Kavazis added, “Physical exercise increases ROS production leading to beneficial cell adaptations. Our data show a similar effect occurs with reproduction, suggesting that reproduction-induced ROS is not necessarily bad.”

From their research on mitochondrial function with the NSF Career Award, Hood and Kavazis predicted that the mitochondria would not work as well following reproduction, but in fact, the data suggested that mitochondrial function was improved. In examining how mitochondrial function changes with reproduction, they found several benefits. Specifically, cells produce more antioxidants, cells repair damage more efficiently, and cells make more mitochondria to adjust to the stress.

“Maybe 70 to 90 percent of mitochondrial damage would have to occur before cell function is impaired,” Hood hypothesized. “We want to find out how the number of reproductive bouts affects mitochondrial function and how different stressors affect mitochondrial function.”

To that end, they designed a study to examine how physical activity impacts reproduction, testing the “carryover effect.” For one month they gave mice a voluntary running wheel and afterwards found that those mice had more mitochondria in their liver, heart, and muscle than the mice without a running wheel. Furthermore, the females that ran before reproduction gave birth to more offspring and those pups had a higher body mass at weaning.

“At weaning, those that ran and reproduced had more mitochondria and increased respiratory function than those that did not,” said Hood. “We were very excited about this finding. Wild animals will run, because of migration, food availability, and weather. All those factors influence activity levels.”

Previously, the researchers had found long-term benefits to mitochondrial performance with lactation in their study from the NIH grant in which they tested the “lactation reset hypothesis.” Kavazis’s doctoral student, Hayden Hyatt, led this project for his dissertation. The data showed that female rats that lactated after giving birth had higher respiration rates in liver mitochondria and lower serum glucose concentration (which can correlate with a lower incidence of diabetes). During gestation the body accumulates adipose tissue, but after birth, the process is reversed and geared toward fat mobilization. This metabolic “reset” did not occur, however, in the rats that did not lactate after pregnancy.

“Women who breastfeed their babies have reduced incidence of obesity, diabetes, heart disease, and cancer than those who do not breastfeed,” said Hood. “It is all tied to mitochondrial performance.”

The next steps with the NSF Career Grant is to better understand how mitochondrial function changes across varying numbers of reproduction bouts with compounding ROS due to additional stressors. The first study will introduce an antigen (isolated from the blood of an invertebrate called a keyhole limpet hemocyanin) in mice that stimulates the immune system, thus making them expend more energy to fight the foreign substance. Hood, Kavazis, and doctoral student Hailey Parry will examine the ROS state within liver and muscle cells, the largest and most metabolically active tissues, to see if they reach the threshold of becoming negative rather than beneficial more quickly.

For the NSF EPSCoR Grant, Hood and Kavazis will be evaluating how genetic variation in an intracellular stress response interacts with reproduction and longevity.

EPSCoR stands for the Established Program to Stimulate Competitive Research. Its purpose is to enhance research competitiveness of targeted jurisdictions by strengthening STEM capacity and capability. It aims to foster collaborations between EPSCoR institutions, thus leading to this collaboration between Auburn University and the University of South Carolina.