Everything slows down as we age. For some lucky folks, aging happens gracefully with nary a disease in sight. For others, the springs start popping off around 40 and by the time we reach ‘old age’ our bodies and brains are barely functioning. Arguably, diet and lifestyle have something to do with how well or how poorly we age, and of course, genetics contribute mightily, but beyond that, we really have no idea what’s happening with aging.
Sure, there are all sorts of physiological systems that become progressively less efficient over time. Wear and tear plays a huge role, but the relationships aren’t linear. There are always outliers. There are folks who, on a diet of smokes and scotch, live well into their nineties with all their faculties intact. Then there are the poor souls who are prodigiously healthy, who eat right and exercise, but yet, whose bodies seem set on wide-scale destruction, where the slightest change in lifestyle risks sending them into a morass of cascading illness. Somewhere in the middle, the rest of us live – sometimes healthy, sometimes not – aging in fits and spurts. What the heck?
From a physiological standpoint, aging is marked by two opposing factors: decreasing hormones and increasing inflammation. Where they intersect, age-related illnesses seem to accrue. Called endocrine senescence, researchers have long noted a relationship between declining hormones and declining immune function (marked by increased and inefficient inflammatory responses). Might there be some truth to the ever-young, hormone peddlers? Could hormones be the key to offsetting the age-induced inflammatory cascades? Possibly.
Hormones and Mitochondria
I just finished writing an extensive paper on acquired mitochondrial illness. Throughout the research, I stumbled upon a short essay linking mitochondrial structure and function to estradiol. More specifically, the rapid estradiol decline common post oophorectomy (ovary removal), fundamentally alters the shape, and ultimately, the function of mitochondria. Researchers found that a rapid decline in estradiol evokes significant damage in the brains (and presumably other organs) of female monkeys. Additional studies using estradiol starved mitochondria from female rodents showed similar shape alterations and consequent declines in brain bioenergetics. Interestingly though, with natural menopause, where estradiol declines more gradually, no such structural changes were observed. In fact, with the more gradual decline in estradiol, the mitochondria appear to increase their production of the lifesaving ATP as a compensatory reaction.
All Paths Lead to the Mitochondria
Recall, from previous posts, that mitochondria take dietary nutrients and oxygen, and change them into the chemical energy (ATP) that is used by every cell in the body. Without ATP, cell function grinds to a halt. So, anything that derails the mitochondria, imperils cell function and initiates cell death. Lack of nutrients, sedentary lifestyle, pharmaceutical, and environmental toxicants, all derail mitochondrial function. Cluster too much cell death together in one tissue or one organ and disease happens. Since mitochondria are in every cell of the body, mitochondrial damage induces disease broadly, but especially in regions with high energy demands like the brain, the heart, the muscles, and the GI system.
The cardinal symptoms of mitochondrial damage include fatigue, weakness, muscle pain, and depression. These are followed by dysregulated systems; a GI system, for example, that overreacts or under reacts or temperature dysregulation (hot flashes, cold insensitivity), insulin/sugar dysregulation, emotional volatility, migraines, seizures, syncope (fainting), and so on. It’s not a pretty picture.
In addition to providing the fuel for cellular respiration, e.g. life, mitochondria control a host of other functions, steroidogenesis is one of them. This means that if we fail to feed the mitochondria or hurl insults at them, hormone dysregulation is inevitable. Ditto for inflammation, as the mitochondria regulate inflammatory cascades. Every woman knows when her hormones are out of whack. Well, now we know that hormone dysregulation emerges from the mitochondria.
From a systems perspective, consider the mitochondria as central regulators of organismal health. Mitochondria both send and receive signals from all over the body and then adjust their functioning accordingly. With their role in hormone synthesis, we would expect there to be cross-talk between the mitochondria and circulating hormones. Indeed, there is. All steroid hormones have receptors on the mitochondrial membranes. When hormone concentrations increase or decrease, the mitochondria will initiate the synthesis of new hormones and send signals throughout the body to adjust other hormone-responsive systems as well.
No Estradiol Equals Misshapen Mitochondria: Donuts and Blobs
Removing the ovaries starves the mitochondria of one of its many feedback mechanisms and damages the brain mitochondria in the regions of the brain responsible for executive function and memory – the frontal cortex and the hippocampus. The mitochondria change shape, from spheres (healthy) to donuts and blobs, which represent early and late-stage mitochondrial damage, respectively. Misshapen mitochondria cannot provide the energy (ATP) needed to perform critical brain functions such as neural communication or the antioxidant tasks needed to clean up toxicants. Neurodegeneration ensues. In layman’s terms, and in the early stages, brain fog and memory loss. Researchers believe that it is this loss of functional mitochondria that contribute to the onset of neurodegenerative disorders like Alzheimer’s and other dementias. And, this loss of function is precipitated by an unnatural loss of estradiol.
Ovary Removal is Common with Hysterectomy – Now What?
For the millions of women who have had their ovaries removed with hysterectomy, this presents a problem. Amid the myriad of other side effects associated with ovary removal, and perhaps, the root cause of these effects, we can add mitochondrial damage and brain mitochondrial damage, specifically. The rapid decline of estradiol, and other hormones, places many women at risk for neurodegenerative disorders like Alzheimer’s. How could this be mitigated?
In animal research, hormone replacement with 17B – estradiol immediately after the ovaries are removed seems to temper the damage, at least in the short term. There are no long-term studies. Similarly, epidemiological studies in human women suggest hormone replacement immediately after open menopause and/or hysterectomy with oophorectomy reduces clinical symptoms associated with the diseases of aging – e.g. the cognitive decline of Alzheimer’s and other dementias. However, since the synthetic estrogens used pharmacologically are different compounds than those produced endogenously (and used in basic and animal research) and because there are no mitochondrial imaging or even mitochondrial function tests done with human females given hormone replacement, it is difficult to compare the two sets of literature.
Some data suggest that the use of synthetic estrogens damages mitochondria and further diminishes the synthesis of remaining endogenous estrogens (the adrenals continue to produce estradiol and other estrogens after the ovaries are removed). Women who have used synthetic estrogens such as those in oral contraceptives and hormone replacement therapies have lower concentrations of endogenous estradiol, estrone, androstenedione, testosterone, and sex hormone-binding globulin. Based upon the aforementioned research, the decline in endogenous hormones would suggest a commensurate derangement in mitochondrial structure and function, but there are no data either way. At the very least, caution is warranted when contemplating the use of synthetic estrogens, particularly in the current environment that is rife with estrogenic chemicals. There are no data on the use of ‘natural’ or ‘bioidentical’ hormones and human mitochondrial function. So, although the animal data are fairly clear, estradiol replacement begun early enough appears to offset the decline in endogenous estradiol, how this translates to human females is not known.
Other Hormones and Additional Pathways
A flaw common to most research in this field is the failure to address the other hormones involved in modulating health. Estradiol is but one of many estrogens produced endogenously. It is also one of many steroid hormones produced in the ovaries and regulated by mitochondrial function. How estradiol removal or add-back affects progesterone, the androgens, or even the glucocorticoids (cortisol) – is not known. Compensatory reactions are likely. Understanding how those reactions mediate mitochondrial function might determine a viable workaround for the depleted estradiol. The beauty of human physiology is a mind-blowing breadth and depth of compensatory reactions to maximize survival. So I would think, and this is purely speculative, that even if one has lost her ovaries, and even if estradiol treatment was not initiated immediately, or if synthetic estrogens were used instead, there should be other mechanisms to tap into and compensate for this loss. That is, there should be multiple pathways to help maintain mitochondrial function. What those are, I do not know, but they are worth exploring.
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This post was published originally in January 2015.