Where does the decline start?
Yes, mitochondria are critical pieces that start to break down.
Sure, the decline of the immune system is front and center (thanks thymus for atrophying).
We have all the different pathways in the news:
- AMPK
- mTOR
- Sirt1
- IGF1 (the hidden power of insulin)
The question is...what is the first chink in the armor?
Let's look at the role of steroidal hormones. Estrogen and Testosterone primarily but also the upstream players like pregnenolone and DHEA.
We'll cover these areas:
- Evolution's priority - post reproduction
- The hallmarks of aging
- The steroidal hormone cascade and longevity
- Estrogen and aging
- Testosterone and aging
- Estrogen and testosterone with mitochondria
- Estrogen and testosterone with NAD
- Estrogen and testosterone with SIRT complex
- Estrogen and testosterone with AMPK/mTOR
- Estrogen and testosterone and IGR1
- Estrogen and testosterone and DNA repair
- Estrogen and testosterone with immune function
- The Vitamin D (a steroid!!) kicker
Let's get started.
Evolution's priority - post reproduction
Steroidal hormones are the complex we generally associate with reproduction.
Testosterone and estrogen get the lion's share of notoriety with progesterone as a powerful counter to estrogen.
Rightfully so..they are big drivers of growth and replenishment in the body.
Here's the deal...Mother Nature is incredibly frugal with genetic and chemical real estate.
If she can re-purpose an existing pathway for reproduction and gender delineation for other tasks, she will.
And she did!
Every cell in your body has estrogen and testosterone receptors on them.
Heart. Brain. Bone. Organ. Immune cells.
Actively engaged with our steroidal hormones second by second.
We covered estrogen and mental health or my estrogen journey as well as testosterone's effect on the body.
Here's the rub.
These steroids are largely responsible for reproduction.
Each species has a set period of time to reproduce and then move out of the way.
Sexual selection is based solely on the advantage that genetic flexibility offers.
If climate changes, the best suited of the next generation will survive and flourish.
Drought. Famine. Environmental changes. War. Conquest. You name it.
The "old guard" or adults can't change their DNA. They're largely static except for the epigenetic control layer that lays just on top of our raw DNA.
Sexual selection is best to adjust according to new needs.
Hence, a fixed lifespan. The species would be a peril (a few 100,000 years ago) if we lived for 100's of years. Not flexible enough from a DNA perspective.
Our ancestors survived the great killing of the dinosaurs. We're nimble, genetically speaking.
Unfortunately, a range of illnesses and degeneration accompanies aging.
Here's the question at the heart of this review?
If our steroidal hormones were to remain at the same level of say...a 25-year-old, would the rest of the complex deteriorate the same way?
Testosterone drops over 1% each year.
Total testosterone levels fall at an average of 1.6% per year whilst free and bioavailable levels fall by 2%–3% per year.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4330791/
And the net effect:
Researchers found men with the lowest testosterone levels had the highest mortality rate, followed by men with the highest testosterone levels.
So...not too low or too high.
Estrogen slowly declines but then plummets around age 50.
When it goes, risks for a host of issues spike.
As a result of a lower level of estrogen, postmenopausal women are at increased risk for a number of health conditions, such as osteoporosis and heart disease.
https://my.clevelandclinic.org/health/diseases/15224-menopause-perimenopause-and-postmenopause
Progesterone, the counterpart to estrogen, declines more like testosterone with levels off 50% by age 40.
We can go into any major system of the body or brain and directly tie reduced levels of either to illness and decline.
That would require a whole separate article.
Before we jump into the world of steroidal hormones, let's look at the hallmarks of aging so can investigate connections.
The hallmarks of aging
First, a top-level definition:
genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/
Okay...some of those we can measure directly:
- Telomeres - the little caps at the end of our DNA
- mitochondria function - the powerplants of our cells
- Senescence - so-called zombie cells that leak out inflammation
- nutrient processing - gut microbiome and barrier drops ineffectiveness
- Genomic instability - basically, DNA repair
We'll look at steroidal hormones for all these.
Those are gears and bolt-level players...what about the net effect of this grinding down?
- Frailty - weakness in bones, muscles, skin, hair, and the like
- Cognitive decline - reduction in memory, thinking speed, etc
- Reduced immune function - infection but remember, our immune system removes cancer!
Okay...we have both the technical and the everyday effects of aging.
Benchmarks against which to look at estrogen and testosterone.
Before we jump into estrogen and testosterone directly, let's introduce the extended family.
The steroidal hormone cascade and players
Our steroidal hormones all start with one substance...LDL cholesterol.
Yes, the so-called "bad" cholesterol.
Don't get us started on that!
Interestingly, studies show that when steroidal hormone precursors are supplemented, cholesterol goes down!
It's like this pathway is so important that the body will try to compensate by retaining more cholesterol.
From cholesterol, we get pregnenolone, the mother of all steroidal hormones.
We did a full review on pregnenolone here since it's so fascinating.
The cholesterol connection??
Cholesterol levels were significantly decreased following treatment with pregnenolone compared with baseline (paired t-test t = 3.53, df = 8, p = 0.008)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427920/
Preg drops as we get older.
A study looked at preg supplementation and cognitive aging in mice:
Moreover, it was recently shown that memory performance was correlated with PREGS levels in the hippocampus of 24-month-old rats
https://d1wqtxts1xzle7.cloudfront.net/49584832/
In that same study, they looked at another downstream player DHEA which as known effects on longevity.
DHEA is the precursor to your androgens (testosterone) and estrogens with big impacts on aging:
In human aging, the reduction of adrenal androgen secretion is accompanied by a host of neuroendocrine–metabolic dysfunctions that include decline in the growth hormone (GH)-insulin-like growth factor I (GH-IGF-I) system (21), thyroid function (22), and immune competence (23), fragmentation of sleep (11), and neuronal loss.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC37415/
That brings us to the stars of our show.
The big movers and shakers in the steroidal hormone complex.
Both genders have estrogen and testosterone albeit at very different levels.
Let's start with the one close to our hearts.
Estrogen and aging
Estrogen cycles throughout life and then drops through the floor late 40's. It can have a roller-coast effect that leads to a brutal perimenopause (how we originally found CBD - that story is here).
It's partner, progesterone, drops slowly and steadily with huge impacts on immune function and every system in the body and brain.
We looked at estrogen's effect on mental health but in general, estrogen has two big roles dependent on the A and B receptors.
- A is pro-growth. Grow. Replenish. Revitalize. The opposite of atrophy.
- B is housekeeping - cardiovascular function, cellular integrity, neurotransmitters, etc
We did a deep dive on estrogen here.
It's known that when estrogen goes (50 and beyond), skin, hair, urinary and vaginal tracts, and just about every other tissue in the body and brain starts to deteriorate and lose its vitality.
That's the pro-growth side!
One example is very telling.
In our brain and nervous system, BDNF is the star player for keeping the brain integrated, robust, and dynamic.
It's the brain's fertilizer.
Serotonin drives BDNF and looks at estrogen's effect on serotonin:
Estradiol is especially nurturing towards serotonin – it stimulates TRPH expression to ensure that enough serotonin is made and suppresses MAO A levels to prolong the longevity of the neurotransmitter.
https://www.zrtlab.com/blog/archive/impact-hormones-serotonin-depression/
This is a known pathway (maybe THE pathway) for depression but you can add dementia, anxiety, sleep issues, and many degenerative diseases tied to aging.
To split out the cause and effect of estrogen deficiency and aging, let's look at specific examples.
Here's a study on long term estrogen replacement after age 50:
Long-term ET is associated with lower all-cause mortality in older women.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219089/
Here's the kicker:
Women have the advantage when it comes to living a longer life. Why that is has been largely unclear, but a new study suggests the key difference is the protective effects of the female sex hormone estrogen.
https://www.healthline.com/health-news/why-women-really-outlive-men#The-bottom-line
All the advantages that women have over men start to disappear around age 50. The time that estradiol flies the coup.
It gets stranger!
A study gave male mice estradiol (our primary estrogen) and extended life by almost 20%:
Treatment of mice with 17-α estradiol (17aE2) results in sex-specific lifespan extension, with an increase in median survival in males of 19%
https://onlinelibrary.wiley.com/doi/10.1111/acel.12786
Clearly, there's more to estrogen than just reproduction!
One note...estrogen gets converted into testosterone (called aromatization) within the male bodily (and especially brain) pretty readily so this may just be a round-about way to supplement testosterone.
Let's look at studies where estrogen is abruptly removed so we can weed out other sources.
Oophorectomy is when the ovaries are removed. This is the primary site of estrogen production in the female body.
So...what happens when women lose their estrogen?
First, the brain:
In the Mayo Clinic Cohort Study of Oophorectomy and Aging, women who had both ovaries removed before reaching natural menopause experienced a long-term increased risk of parkinsonism, cognitive impairment or dementia, and depressive and anxiety symptoms.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716666/
More generally:
women who underwent oophorectomy before age 46 years experienced an accelerated rate of accumulation of the 18 chronic conditions considered together
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777385/
They were trying to piece out cause and effect.
The conclusion:
Our findings suggest that bilateral oophorectomy is causally linked to accelerated aging.
Goodness! Can we drop the mic (for half the population at least).
As for the physical:
Bilateral oophorectomy causes an alteration of several fundamental aging processes at the cellular, tissue, organ, and system levels, leading to multimorbidity, frailty, and reduced survival.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734081/
Did we just laundry-list our hallmarks of frailty above?
What about the all-important immune system?
Hormone deficiency in post-menopausal women may cause an impaired immune response, and ERT can restore this phenomenon. Estrogen seems to have an important role in the regulation of immune function.
https://pubmed.ncbi.nlm.nih.gov/15284002/
Remember, the immune system fights infection but it also rebuilds, repairs, and removes pre-cancerous or virally infected cells.
A master architect and builder! Especially in the brain. See CBD and neuroinflammation to learn more.
We didn't even touch on the cardiovascular system where estrogen and progesterone literally shape the heartbeat!
Stoke. Heart attack. COPD. Leading causes of age-related deaths for women. See CBD and perimenopause heart health here.
Okay...we could go on and on. We'll really drill down into the mechanisms at play below.
Let's turn to testosterone first.
Testosterone and aging
What about the male counterpart?
Men have 25 times more testosterone than women although women still need it.
It has many similarities with estrogen as a steroid...a supporter of building, repair, and replenishment.
Testosterone peaks around 18-25 and slowly drops to a very low level where it plateaus.
Testosterone has long had a bad rap due to steroid (for weight lifting) connotations.
First, those are synthetics and synthetics carry a huge and nasty side effect profile (same goes for synthetic estrogens and progestins - see review on estradiol safety).
Secondly, they are delivered at massive levels...way more than what the body is accustomed to.
We're talking about maintaining mid-range testosterone levels.
The question is...why not keep testosterone at a 25 year's old level?
Let's dig in.
First, we have testosterone receptors on every cell of the body and brain.
It's not just about libido and body hair (that's more DHT which we'll get into).
As for longevity, we can get clues from men who naturally have a deficiency in testosterone called hypogonadism.
Hypogonadal men have lower life expectancy than men with full androgenization and cardiovascular disease, obesity or diabetes is often associated with hypotestosteronemia. Low testosterone level is risk factor for these diseases
https://pubmed.ncbi.nlm.nih.gov/27734705/
This is important as it shows key systems that rely on testosterone to function:
- Cardiovascular - heart, arterial health
- Metabolic - fat, cholesterol, energy
- Diabetes - insulin, and sugar
Is this a coincidence? Some other factors besides testosterone?
Not so fast:
It was found that testosterone replacement therapy of men suffering from late-onset hypogonadism increased survival rate by 9-10% in 5 years, similar to that of eugonadal, non-LOH men with normal endogenous testosterone secretion.
https://pubmed.ncbi.nlm.nih.gov/25892327/
So...by supplementing testosterone in men with deficient levels, it boosted their survival rate up to men with normal levels.
But way...if our testosterone is dropping about 10% each decade (so 30% reduction by age 50), are we all essentially testosterone deficient?
After all, the issues above with low testosterone (obesity, heart issues, diabetes) directly track age in terms of risk.
Let's turn to our favorite area...the brain.
There's a known correlation between depression and reduced testosterone:
The relationship between depression and testosterone appears to partly depend upon the androgen receptor genotype of the patient, and in appropriate patients with low testosterone levels, testosterone substitution can increase positive mood and decrease negative mood.
https://pubmed.ncbi.nlm.nih.gov/17178554/
We know serotonin (see serotonin review) is a big player with depression (see depression pathways) and general brain function in general.
Does testosterone have a similar effect on serotonin as estrogen (supportive)?
that men with high levels of testosterone have higher cerebral serotonergic tonus.
https://pubmed.ncbi.nlm.nih.gov/28426945/
Tonus is important. It's the base level of a neurotransmitter. The ocean level as opposed to the waves.
We've written in detail how BDNF is the star of the brain party...our brain's fertilizer.
It is THE key to mental health and addiction.
Speaking of addiction:
The decrease of testosterone serum levels during alcohol withdrawal (days 1–7) was significantly associated with the BDNF serum levels
https://psycnet.apa.org/record/2016-39023-001
There's lots of research on testosterone and BDNF.
We almost can skip over testosterone and frailty. But we won't.
Low Free Testosterone Predicts Frailty in Older Men: The Health in Men Study
https://academic.oup.com/jcem/article/95/7/3165/2596242
What about the all-important immune system?
We'll discuss further below that testosterone has a powerful management role here:
Endogenous testosterone appears to be immunomodulatory rather than immunosuppressive.
https://pubmed.ncbi.nlm.nih.gov/27465811/
It's one direction in its effects which is really important.
This makes sense.
In the female body - estrogen boosts immune response but progesterone counters this.
Males don't have this yin/yang setup so testosterone adjusts according to the state of the system.
The metabolic pathway is really fascinating.
After all, most of the age-related diseases for men like within this pathway.
Obesity. Diabetes. Cardiovascular issues as a result.
Testosterone has a powerful management function here.
Let's walk right it:
Epidemiological studies have established that low testosterone/low sex hormone-binding globulin can predict the development of the metabolic syndrome
https://www.nature.com/articles/hr201052
That's diabetes.
Does it really come down to testosterone and not something else?
A number of studies have found an inverse relationship between the severity of the metabolic syndrome and plasma testosterone
Okay...the tie grows deeper.
Low testosterone levels are associated with increased fat mass (particularly central adiposity) and reduced lean mass in males.
https://pubmed.ncbi.nlm.nih.gov/25982085/
The central adiposity is important. It's belly fat!
A known harbinger of bad things for men.
Decreased muscle mass and increased central adiposity are independently related to mortality in older men
https://academic.oup.com/ajcn/article/86/5/1339/4651053
Even cancer!
Okay...we've covered some of the broad strokes around estrogen and testosterone for longevity.
Let's take this where no one else seems to go...to known longevity pathways that everyone's all abuzz about.
We'll start with the powerplants of the cells.
Estrogen and testosterone with mitochondria
Mitochondria are in contention for being the first link to go as we age.
They are the descendants of ancient bacteria that our ancestors hijacked to power their complex cells.
They even have their own DNA and this is where the issue lies.
It's a simple ring of DNA with very poor error correction as opposed to our more robust system.
The simpler the DNA, the less robust the repair side.
As errors accumulate with mitochondria, they produce less energy for our cellular housekeeping.
We thought THIS might be the first shoe to drop. We have systems that go through and look for malfunctioning cells (immune system) but eventually, the tide turns.
Why do we even bring this up?
Oh, just this…
Estrogens regulate the expression of genes, including miRNAs and lncRNAs, that regulate mitochondrial functions: metabolism, OXPHOS, apoptosis, UPRmt, fission, and fusion. ... Nuclear-encoded miRNA and lncRNA regulate mtDNA-encoded as well as nuclear-encoded transcripts thus functioning as anterograde signals.
https://www.sciencedirect.com/science/article/pii/S2213231719309474
That's a mouthful. Like we said...deep in the weeds.
Basically, estrogen manages the genes needed to keep mitochondria functioning well, in sufficient numbers, and remove those that don't (apoptosis).
This is huge...estrogen is a key manager of our cellular power systems!
What about testosterone?
Our results showed that testosterone increased cell survival and reduced nuclear fragmentation and chromatin condensation. These effects were accompanied by preservation of mitochondrial function and an augmented expression of neuroglobin.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4921852/
The same effect from different vantage points. Fewer errors in replication (mitochondria are prolific replicators - even a bout of exercise will increase your mitochondria).
There are dozens of studies on individual components but the net-net is that estrogen and testosterone are needed to keep mitochondria functioning well.
Reproduction indeed.
This is key to the whole "zombie" or senescent cell issue.
There's a whole swift of the longevity push right now that's focusing on removing these dysfunctional cells from the body.
The molecules are called senolytics (see fisetin as an example).
Much newer research is finally piecing this all together:
Collectively, our data establish independent roles of estrogen deficiency and cellular senescence in the pathogenesis of osteoporosis
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697189/
Essentially, when estrogen goes down, these senescent or zombie cells build up and the net effect is osteoporosis!
This is very exciting research.
What about testosterone? Again, a 2020 study:
Testosterone Protects Pancreatic β-cells from Apoptosis and Stress-Induced Accelerated Senescence
https://www.wjmh.org/pdf/10.5534/wjmh.200169
Mitochondria dysfunction is thought to play a big role in the increase of senescent cells.
Let's dive down into the mitochondria's key output which is all the rage with longevity buffs.
NAD.
Estrogen and testosterone with NAD
We said that mitochondria make energy but in what form?
There's a whole complex of chemical magic that resolves around NAD+...the raw unit of energy for our cells.
It's currently a gigantic market for supplementation between NAD, NMN, and the likes.
The basic theory is that as our energy production goes down, it sends signals to starting winding other pathways down.
To wit:
Accumulating evidence has demonstrated that NAD is a key molecule involved in governing the aging process in many organisms. Recent studies have suggested that the intermediates of NAD metabolism, as well as NAD-related metabolites, also possess some unique biological functions in aging and longevity regulation.
https://www.sciencedirect.com/science/article/pii/S1568163718300060
So...what about estrogen and testosterone?
Okay...this is going to force us to get our hands dirty.
Remember that estrogen turns genes on and off. One of them is called BMAL1 which manages a range of nutrient pathways including….NAD+
BMAL1 also activates genes involved in the production and utilization of nutrient metabolites, including the NAD+ biosynthetic enzyme NAMPT, and NAD+ is an important cofactor for the metabolic regulators SIRT1 and PARP1, which mediate rhythms of oxidative metabolism.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649786/
Remember that SIRT1 item...we'll come to it later.
The key between estrogen and NAD+ production is indeed this SIRT1 pathway.
What about testosterone?
We observed that an NAD(+)-dependent deacetylase, SIRT1, played an important role in the protective effect of testosterone against oxidative stress-induced endothelial senescence.
https://pubmed.ncbi.nlm.nih.gov/22238626/
There's that SIRT1 again. Let's go there since it's probably the biggest longevity buzz right now. Even Dr. David Sinclair (our favorite) is a big singer of praise.
Estrogen and testosterone with SIRT1 complex
This is all coming together.
SIRT1, part of the sirtuin suite of genes is probably the closest thing we have to a longevity gene.
- Mitochondria make our energy
- NAD+ is the unit measure of this energy
SIRT1 is a manager of energy production and consumption.
It is known now that sirtuins, when adjusting the pattern of cellular metabolism to nutrient availability, can regulate many metabolic functions significant from the standpoint of aging research – including DNA repair, genome stability, inflammatory response, apoptosis, cell cycle, and mitochondrial functions.
https://www.sciencedirect.com/science/article/abs/pii/S1896112615000504
Wow.
- DNA repair. Check
- DNA stability. Check
- Inflammation (a key hallmark of aging). Check.
- Removing bad cells (apoptosis). Check
- Cellular birth/death balancing. Check
Finally, mitochondria...everything we've been discussing above.
This was really the breakthrough in longevity where it looked like we could actually have some real effect on the process.
It started with yeast where boosting sirtuins could extend lifespan by 70%.
This is a highly conserved pathway and humans have a complex and robust sirtuin pathway.
Sirtuins are the real player
With similar effects:
We observed a significant increase in the SIRT1 level in older people and found a significant positive correlation between SIRT1 level and age in the overall studied population.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365019/
That speaks to genetic and environmental differences but we can nudge this pathway on through a series of different ways.
- Caloric restriction
- Cold and heat exposure
- Certain supplements and medications
We'll speak to sirtuins role to play in a bigger system but let's focus on estrogen and testosterone.
First, estrogen.
A study on the aging mind found the following:
The results indicate that 17β-estradiol, by stimulating ERα/SIRT1, halts d-gal-induced oxidative stress–mediated JNK/NF-ҡB overexpression, neuroinflammation and neuronal apoptosis.
https://www.mdpi.com/2073-4409/8/8/928/htm
Let's break that down, shall we?
Estradiol (our primary estrogen) was able to calm brain inflammation (which is key to mental health and decline - see CBD and neuroinflammation) and even the death of neurons (apoptosis).
It did this through SIRT1!
Bone loss is a known issue with estrogen deficiency.
7β-Estradiol replacement therapy may treat postmenopausal osteoporosis by improving osteoblastic cell function via the Sirt1/NF-κB/MMP-8 pathway.
https://www.tandfonline.com/doi/abs/10.1080/13697137.2020.1758057
There's SIRT1 again!
SIRT1 is a systemwide player so we can expect a similar response throughout.
It gets more interesting.
Brand new research is showing that sirtuin-inducing chemicals like resveratrol may have their effects via...estrogen pathways!
Hence dSTACs’ intrinsic oestrogenicity may underlie their proven ability to impart the health benefits of oestradiol, and also provides a mechanistic insight into how they extend healthspan or protect against MARDs.
https://www.nature.com/articles/s41598-020-62162-0
This is 2020 research but we need to break it down.
They're basically saying that the health benefits of substances like resveratrol (DSTACs) are due to their imitation of estrogen! The estrogen A receptor (see our review of estrogen).
This is the growth and replenishment side.
Goodness...this is groundbreaking and speaks to our steroidal hormone theory as the first piece to drop with aging.
What about testosterone?
A study looked at aging of brain cells (neurons) and vascular tissue:
Testosterone increased eNOS activity and subsequently induced SIRT1 expression. SIRT1 inhibited endothelial senescence via up-regulation of eNOS
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0029598
eNOS is a form of nitrous oxide...key for cardiovascular health.
Basically, testosterone boosted SIRT1 which saved the "skin" of our inner plumbing!
There are known benefits for testosterone and full cardiovascular health.
Here's where it gets interesting.
SIRT1 has a powerful effect on boosting estrogen and testosterone!
Together, these findings suggest that Sirt1-disruption results in a sharp decrease in testosterone and influence the sexual behavior of male mice, which is very similar to the symptoms of late-onset hypogonadism (LOH) (Swee and GAN, 2019).
https://link.springer.com/article/10.1007/s13238-020-00771-1
Okay...reduce SIRT1 and lose testosterone production.
Same thing with estrogen.
This brings us full circle and really begs the question...what is the purpose of SIRT1?
Let's introduce the most important system you'll definitely want to know (and stimulate).
Estrogen and testosterone with AMPK/mTOR
It's all about reproduction...from an evolutionary design, that is.
SIRT1 is a big player in the AMPK pathway. Maybe the lead role.
AMPK is a whole series of cascading systems that are triggered during bad times.
Famine. Drought. Extreme heat or cold. When survival is fraught with peril.
What's the connection with steroidal hormones?
Basically, the worst time to have babies!
So the body saves it for another day.
All systems move from reproduction to conservation and every cell in the body is thrown into extreme housekeeping mode.
Batton the hatches!
- Energy is conserved - NAD+ production is more efficient, mitochondria are pruned and fine-tuned
- Cellular machinery is dialed in - senescent cells are removed. Faulty cells (hello, cancer) are removed
- Immune system is tightened up and supported
Interestingly….steroidal hormones are boosted!
That's testosterone and estrogen.
Why?
Again, it's all about reproduction and if it's a bad time to have babies now (famine, drought, etc), extend the reproductive period for later.
It's that simple. A delay in reproductive health and all the machinery needed to make that happen.
Look at all tricks we have in our current longevity toolkit.
- Intermittent Fasting - temporary famine - AMPK
- Cold exposure - AMPK
- KETO diet - a form of fasting - the whole metabolic complex is balanced by AMPK - energy conservation after all
- Calorie restriction - fasting - AMPK
- Exercise?? Physical and energy complex stress - AMPK
This is all about delaying aging so we can hopefully survive the current situation and reproduce in the future.
Hence..
We demonstrate that E2 activates AMPK via an ERβ/Ca(2+)/CaMKKβ-dependent pathway in endothelial cells.
https://pubmed.ncbi.nlm.nih.gov/25616441/
And Testosterone?
Testosterone Increases the Expression and Phosphorylation of AMP Kinase α in Men With Hypogonadism and Type 2 Diabetes
https://pubmed.ncbi.nlm.nih.gov/31858126/
That's an interesting jumping point.
Our metabolic complex (sugar, insulin, fat creation, cholesterol, etc) is a powerful mirror to our aging status.
Especially insulin!
Let's touch on mTOR, another adjacent system to AMPK.
Remember the big rapamycin craze for longevity? That's the "R" in mTOR.
Here's the import:
mTOR has been implicated in many of the processes that are associated with aging, including cellular senescence, immune responses, cell stem regulation, autophagy, mitochondrial function, and protein homeostasis (proteostasis)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611156/
- Senescence - killing off faulty cells
- Autophagy - cellular suicide when dysfunctional
- Mitochondria - energy production and oxidative stress
- Proteins - a big deal - see Dr. Sinclair's Yamanaka factor research (gamechanger)
Rapamycin basically slows down mTOR pathways for its beneficial effects.
The tricks above such as calorie restriction also rely on mTOR activity.
Like AMPK, mTOR is a nutrient sensor...how are things going in the energy complex out there!
So...what about the steroidal hormones?
So mTOR is all over the metabolic complex and we see powerful effects of estrogen and testosterone on this entire pathway:
Estrogen modulates abdominal adiposity and protects female mice from obesity and impaired glucose tolerance
https://link.springer.com/article/10.1007%2Fs00394-011-0266-4
Belly fat. Glucose issue (pre-diabetes).
Remember the calorie restriction (called hypophagia) effect on aging (slows significantly)?
Hello, estrogen:
Overall, these data indicate that E2 induces hypophagia through modulation of mTOR pathway in the ARC.
https://joe.bioscientifica.com/view/journals/joe/238/3/JOE-18-0190.xml
Goodness. The ARC is a key area of the hypothalamus that acts as a regulatory hub for multiple functions.
mTOR is ultimately controlled by AMPK so we can reference its interplay above with estrogen and testosterone:
mTOR activity is also controlled by the 5′-AMP-activated protein kinase (AMPK) complex, the main energy sensor of the cell
https://academic.oup.com/endo/article/154/12/4594/2433343
Check out our review on metformin (AMPK), berberine (AMPK), and fisetin (mTOR).
Speaking of energy use...
Let's jump there now for a current aging marker - IGF1.
Estrogen and testosterone and IGF1
First, the relevance:
Several preclinical studies reported that mutation in genes controlling the GH/IGF-1/insulin signaling pathway can significantly increase lifespan in both invertebrate and vertebrate animal models
https://www.frontiersin.org/articles/10.3389/fendo.2019.00027/full
IGF1 is short for Insulin Growth Factor and it's a key player in our energy system.
AMPK is all about energy balancing.
IGF1 is the gas pedal for the energy complex:
As a major growth factor, IGF-1 is responsible for stimulating growth of all cell types and causing significant metabolic effects
https://en.wikipedia.org/wiki/Insulin-like_growth_factor_1
As we age, it starts to go down...as it goes, so do we.
An example in the brain:
Recent findings suggest IGF-1 is essential for neurogenesis in the adult brain, and this reduction of IGF-1 with ageing may contribute to age-related cognitive decline.
https://pubmed.ncbi.nlm.nih.gov/29233786/
You won't find bigger fans of neurogenesis than us - key to addiction and mental health.
See CBD and neurogenesis or CBD and brain repair.
This is a systemwide player though and its effects are similar everywhere.
Beyond puberty, it's the repair crew from daily wear and tear.
First, the tie with AMPK:
Insulin-like growth factor-1 activates AMPK to augment mitochondrial function and correct neuronal metabolism in sensory neurons in type 1 diabetes
https://pubmed.ncbi.nlm.nih.gov/30545741/
What about estrogen and testosterone - similar supports of growth/repair?
Look at what happens when estrogen leaves the stage (late 40's):
Indeed, in the post-menopausal woman loss of estradiol coincides with increased disorderliness of GH secretion and a diminished negative feedback control of IGF secretion.
https://www.frontiersin.org/articles/10.3389/fcell.2021.630503/full
And testosterone:
Serum bioavailable testosterone concentration was positively correlated with serum IGF-1 level
https://pubmed.ncbi.nlm.nih.gov/29992746/
This isn't surprising as all three are "pro-growth"...again, the opposite of atrophy as we age.
We could fall down a rabbit hole of metabolic effects (glucose, brown fat, insulin, lipids, etc) of testosterone and estrogen but let's go down further into the machinery.
To the code itself!
Estrogen and testosterone and DNA repair
We've been floating above in pretty big systems like AMPK but let's dive down into DNA repair itself.
We'll start with our root programming...the DNA itself.
As we age, errors accumulate but we have a whole system to detect and repair these.
This system starts to buckle with age:
Accumulating evidence suggests that loss of genomic maintenance may contribute to aging, especially in the central nervous system (CNS) owing to its low DNA repair capacity.
https://pubmed.ncbi.nlm.nih.gov/29311911/
First, let's look at the sworn enemy of DNA...oxidative stress. Little chemical scissors of various oxygen configurations that slice and dice DNA (as well as our cells in general).
Scientists show that estrogen clearly protects the brain and its DNA from oxidative stress:
Remarkably, OVX blunted the differences in peroxide and GSH levels between females and males while estrogen treatment prevented them, highlighting the protective effects of this steroid against oxidative stress
https://www.frontiersin.org/articles/10.3389/fnagi.2017.00430/full
Basically, women fare much better than men till menopause (loss of estrogen), and then risks for a range of issues including dementia run higher.
Estrogen supplementation protected against this!
As for DNA repair itself, there's quite a bit of research regarding estrogen's effect:
Moreover, in patients with basal cell carcinoma, postmenopausal women show a significant drop in lymphocyte DNA repair capacity compared to postmenopausal women on estrogen supplementation
https://www.frontiersin.org/articles/10.3389/fnagi.2017.00430/full
To summarize:
various studies have reported that sex steroids, particularly estrogen and progesterone, regulate DNA repair mechanisms in the brain.
To put a point to it:
Estrogen not only regulates the expression/activity of DNA repair enzymes, but it has also been described to regulate their subcellular distribution.
Look...we have to pick just a few examples from literally 100's of specific pathways in that link.
Read through it...it's fascinating just how important estrogen is to this system.
What about our male counterpart testosterone?
If you need an example that mother nature uses reproduction health as the trigger for aging…
Androgen suppression mediates transcriptional downregulation of DNA repair genes.
https://pubmed.ncbi.nlm.nih.gov/27166396/
Reduce testosterone function...reduce DNA repair.
Or in the prostate:
Our results indicated that under oxidative stress androgen signaling may induce apoptosis by activating the DNA damage response.
https://pubmed.ncbi.nlm.nih.gov/27166396/
Remember the chemical scissors (a byproduct of our energy production by the way)...oxidative stress?
Testosterone activates DNA repair to deal with the fallout.
A quick detour. Much of the early research focused on cancer (partially a result of faulty DNA repair process).
The prostate is front and center with testosterone. It's DHT however, a very powerful converted version of testosterone, that drives issues in the prostate.
This conversion of DHT is dependent on an enzyme called 5AR which can be inhibited.
The big hair loss meds essentially work this way as does pumpkin seed oil.
Okay...back to DNA repair.
Let's now look at the next level up...epigenetics.
This is where the exciting work of Dr. Sinclair and Yamanaka factors is occurring.
Essentially, the control layer that turns genes on and off.
Our DNA is tightly wound up and a system called histones manages the brief unwinding to expose the right genes that need to be read into proteins so they can do their work.
"Right genes" is the catch with longevity.
Over time, this process accumulates errors, and Sinclair's work points to ways of resetting this system. See the full review here. It's the most exciting thing we've seen in longevity research or health in general since CRISPR.
So...what does this have to do with estrogen and testosterone?
We can quickly fall deep into the weeds here but just some highlights, please.
sex-steroid hormone 17β-estradiol (E2) to enhance memory formation is dependent on histone acetylation and DNA methylation, a finding that has important implications for understanding how hormones influence cognition in adulthood and aging.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360196/
They are literally saying that memory formation depends on estrogen's interaction with this histone (folding/unfolding DNA) correctly.
Acetylation is the unraveling of DNA to expose areas for interaction. Methylation is the active process of engaging our genes.
Methylation tends to decrease globally with age (not enough gene expression). The B vitamins are especially important here.
Acetylation also decreases with age...especially in the brain.
Maybe now we know why (hint hint...the estrogen effect above as ONE example).
And testosterone is all over the DNA repair process even at the epigenetic level:
DNA damage-activated AR was found herein to promote the expression of numerous genes associated with DNA repair
https://cancerdiscovery.aacrjournals.org/content/3/11/1254
AR is short for androgen receptors (where testosterone plugs into).
Among that suite of repair pathways (very complex), H2AX triggers the DNA epigenetic repair process and testosterone's role:
Androgen treatments increased H(2) O(2) -induced activation of the DNA damage response and PARP cleavage, but not when the H(2) O(2) -treated cells were also treated with the anti-androgen flutamide.
https://pubmed.ncbi.nlm.nih.gov/22290195/
This is important...basically, they were able to negate this DNA repair process by blocking testosterone's activity.
Keep in mind that testosterone is converted into estrogen even in male bodies.
You need both for either gender...just in different ratios!
One last piece.
Estrogen and testosterone with immune function
The future of health (even mental health) research is the immune system. See CBD and neuroinflammation to learn more as one example.
This is one of the initial shoes to drop with aging.
In fact, a whole swath of research focuses on the shrinking thymus as a key market of aging.
The thymus acts like headquarters for the dispatch of immune agents.
On the flip side, aging is associated with a general systemic inflammation. Inflammaging as it's so-called.
During aging, chronic, sterile, low-grade inflammation - called inflammaging - develops, which contributes to the pathogenesis of age-related diseases.
https://pubmed.ncbi.nlm.nih.gov/30046148/
Interestingly, the gut bacteria and environment serve as a thermometer of inflammation for the rest of the body.
Check out our reviews on the gut barrier and gut inflammation.
So...how do estrogen and testosterone figure into this piece?
A few points first with estrogen.
In general, estrogen tends to boost immune response while its counterpart, progesterone, calms immune response.
The latter is critical to autoimmune and inflammatory diseases that accompany age.
First, estrogen is all over our immune response:
There is now an enormous amount of literature on estrogen’s effects on the cells of the innate immune system [neutrophils, macrophages/monocytes, natural killer cells, dendritic cells (DC)], and the adaptive immune system (T and B cells).
https://www.frontiersin.org/articles/10.3389/fimmu.2015.00635/full
Just for reproduction indeed.
That review reflects a litany of direct effects on every corner of the immune system.
In general, as we age, our immune system loses robustness. This is called immunosenescence.
Estrogen is a direct supporter of immune activity. To cut to the chase:
HRT reverses the menopausal CD4/CD8 ratio and also limits the general peri- and postmenopausal inflammatory state.
https://pubmed.ncbi.nlm.nih.gov/34371873/
And the gut barrier and inflammatory state?
Progesterone and estrogen improved wound healing and epithelial barrier function in intestinal epithelial cells via upregulation of tight junction proteins.
https://pubmed.ncbi.nlm.nih.gov/30893871/
Goodness. Remember that the gut is generally the way in for bacteria, viruses, and more than our body had to deal with through inflammation.
What about testosterone?
Again, many effects across the range of immune response pathways (varied indeed).
The one we want to focus on for inflammaging:
(1) testosterone deficiency was associated with an increase in pro-inflammatory cytokines; (2) testosterone substitution reduced pro-inflammatory cytokines.
https://pubmed.ncbi.nlm.nih.gov/29925283/
That's a reduction. However, testosterone has known effects on fighting various diseases and supporting immune response.
For this reason, testosterone is an immunomodulator...not purely a suppressor or booster.
A study looked specifically at testosterone to see if it was the key to why 8 out of 10 autoimmune sufferers are women:
We proved that androgens were the hormones giving male mice that double layer of protection from inflammation.
https://www.sciencedaily.com/releases/2021/05/210512142846.htm
Okay...we covered a lot there.
We didn't spend time on progesterone (full review here) but it works hand in hand with estrogen. You can't have one without the other.
In fact, progesterone helps to protect against some of the pro-growth issues with estrogen!
One note...both estrogen and testosterone help with obesity and body fat...especially belly fat.
Remember that aging is associated with low level, chronic inflammation:
Excess fat is known to be associated with disease, but now the researchers have confirmed that fat cells inside the abdomen are secreting molecules that increase inflammation. It's the first evidence of a potential mechanistic link between abdominal fat and systemic inflammation.
https://source.wustl.edu/2007/03/belly-fat-may-drive-inflammatory-processes-associated-with-disease/
Per Mayo Clinic:
Many women also notice an increase in belly fat as they get older — even if they aren't gaining weight. This is likely due to a decreasing level of estrogen, which appears to influence where fat is distributed in the body.
https://www.mayoclinic.org/healthy-lifestyle/womens-health/in-depth/belly-fat/art-20045809
And testosterone seems to be directly in charge of this:
After 6 weeks a dramatic decrease of abdominal LPL was found, as well as an increase in the lipolytic responsiveness to norepinephrine, both changes confined solely to the abdominal, and not femoral adipose tissue regions.
https://pubmed.ncbi.nlm.nih.gov/1778664/
Let's turn to the kingmaker of steroidal hormones. Vitamin D.
The Vitamin D (a steroid!!) kicker
We already did a giant review of D but it's worth mentioning for both longevity and in context with estrogen and testosterone.
Vitamin D is a steroid! One we get from the sun.
Its effects on longevity are well known...always with the C Elegans worms first:
"Vitamin D engaged with known longevity genes -- it extended median lifespan by 33 percent and slowed the aging-related misfolding of hundreds of proteins in the worm"
https://www.sciencedaily.com/releases/2016/10/161025125102.htm
Let's combine fat accumulation (remember the belly fat piece) and AMPK and SIRT1:
Vitamin D Ameliorates Fat Accumulation with AMPK/SIRT1 Activity in C2C12 Skeletal Muscle Cells
https://pubmed.ncbi.nlm.nih.gov/31744213/
Check. Check. Check.
In fact, Vitamin D is so integral to our health that it has effects across a range of pathways.
Vitamin D Promotes Protein Homeostasis and Longevity via the Stress Response Pathway Genes SKN-1, IRE-1, and XBP-1
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689451/
And the tie with aging itself?
Aging reduces vitamin D production in skin. There is a decrease in the concentration of 7-dehydrocholesterol in the epidermis in old compared with young individuals and a reduced response to UV light, resulting in a 50% decrease in the formation of previtamin D3
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782116/
Here's the crazy part
A majority of the US population is deficient and that's based on the ridiculous RDA requirements for rickets and bendy knees!
Endocrinologists want us closer to 70-80 ng/ml! The RDA recommends 30. The Massai tribe is over 100 and they live very much like our ancestors did...8-10 hours of direct sunlight.
Here's the kicker...estrogen and testosterone are completely intertwined with their distant cousin Vitamin D:
Heart and Bone Damage From Low Vitamin D Tied to Declines in Sex Hormones
Bone. Heart. Brain. Immune system!
Compared to men with low 25(OH)D serum level (< 20 ng/mL), vitamin D replete men (30–39.9 ng/mL) had significantly lower risk of very low NKA
https://www.frontiersin.org/articles/10.3389/fimmu.2021.594356/full
Natural Killer cells. They're kinda important for immune response to infection!
All this makes you wonder if Vitamin D production is the first shoe to drop which leads to deteriorating estrogen/testosterone.
Afterall…
These results indicated that vitamin D is essential for full gonadal function in both sexes. The action of vitamin D on estrogen biosynthesis was partially explained by maintaining calcium homeostasis; however, direct regulation of the expression of the aromatase gene should not be neglected.
Or…
Vitamin D deficiency leads to reduced production of testosterone. The results of the study showed that the blood concentrations of testosterone and vitamin D were linked among the 300 healthy men with normal testosterone production
https://sciencenews.dk/en/vitamin-d-increases-testosterone-production
It's a chicken or the egg question but the sun (Vitamin D) definitely came first!
Check out our longevity toolkit review and the look at Dr. Sinclair's new research which we think will completely rewrite the entire longevity field...similar effect to that of CRISPR!
Be well. Take care of each other. Take care of yourself.
Always work with a doctor or naturopath with any supplement!
The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.