Estrogens are crucial for skin health due to their ability to modulate collagen synthesis. They have been shown to increase the activity of fibroblasts—cells responsible for producing collagen and elastin in the dermis—which enhances skin elasticity and hydration.

Studies have shown that estrogen therapy can increase collagen production in postmenopausal skin by approximately 48% after six months of treatment.

Dr. Galán – Neolife Medical Team

During menopause, collagen levels drop significantly, affecting both skin elasticity and hair density and quality.

Menopause is a transitional period in a woman’s life characterized by a decline in the production of sex hormones such as estrogens, testosterone, and progesterone. These hormones play fundamental roles in the homeostasis of various tissues, including skin and hair, which undergo noticeable changes during this phase.

The skin, the largest organ in the human body, and hair follicles highly depend on proper hormonal balance, particularly in terms of collagen synthesis and preservation. Collagen is an essential structural protein that provides elasticity, firmness, and strength. Its loss can lead to noticeable aesthetic changes such as wrinkles, skin laxity, and hair thinning.

Collagen in Skin and Hair

Type I and Type III collagen are the two predominant forms found in the dermis and play a vital role in maintaining skin’s structural integrity. The collagen fiber network not only provides mechanical support but also facilitates cellular regeneration, particularly in hair follicles. During menopause, collagen levels drop significantly, impairing skin elasticity and hair quality. Dermal collagen loss with age contributes to reduced follicle viability and a shorter anagen (growth) phase of the hair cycle, resulting in thinner, more fragile hair.

Changes in Postmenopausal Collagen Levels

Numerous studies have shown that, within the first five years after menopause onset, women experience up to a 30% reduction in dermal collagen, especially in the face and neck area (Brincat et al., 2005). This phenomenon is more pronounced in sun-exposed skin due to the combination of hormonal decline and accumulated UV damage. Accelerated postmenopausal skin aging is associated with decreased collagen and elastin synthesis, leading to a greater susceptibility to wrinkle formation, increased skin fragility, and noticeable volume loss in the facial area.

Additionally, in the scalp, the decline in sex hormones and collagen loss contribute to hair follicle miniaturization, a pathological process that can result in excessive hair shedding and the development of diffuse or female-pattern baldness.

The Role of Estradiol in Skin and Hair Health

Estrogens are crucial for skin health due to their ability to modulate collagen synthesis. Studies have shown that estrogens increase fibroblast activity, the cells responsible for producing collagen and elastin in the dermis, which improves skin elasticity and hydration (Thornton, 2013). Estradiol (E2) enhances fibroblast activity by binding to its specific receptors, primarily ER-α and ER-β. These receptors activate intracellular signaling pathways such as PI3K/Akt and MAPK/ERK, promoting fibroblast proliferation and differentiation. Additionally, estradiol stimulates the production of growth factors like TGF-β (Transforming Growth Factor Beta), which in turn increases Type I and III collagen synthesis.

• Increased collagen production: Studies have demonstrated that estrogen therapy can increase collagen production in postmenopausal skin by approximately 48% after six months of treatment (Phillips et al., 2001).
• Impact on skin elasticity: Research has shown an increase in skin elasticity and thickness, along with a reduction in collagen fiber fragmentation, thereby improving skin firmness and resilience.

Estrogens also play an important role in regulating matrix metalloproteinases (MMPs), enzymes that degrade collagen fibers. MMPs, particularly MMP-1 (collagenase), MMP-3, and MMP-9, break down collagen in the extracellular matrix. During menopause, the decline in estrogen levels increases the activity of these enzymes, accelerating collagen degradation. Estradiol modulates MMP expression through estrogen receptor (ER) pathways, inhibiting MMP gene transcription and promoting the activity of tissue inhibitors of metalloproteinases (TIMPs), which helps preserve collagen integrity and delay wrinkle formation.

Additionally, estrogens prolong the anagen phase of the hair cycle—the active growth phase—contributing to denser and more voluminous hair.

The Role of Testosterone in Skin and Hair Health

• Sebaceous Secretion

Testosterone stimulates the sebaceous glands, increasing sebum production. In postmenopausal women receiving testosterone therapy, an increase in sebaceous gland activity has been observed. This effect is due to the conversion of testosterone into dihydrotestosterone (DHT) by the enzyme 5-alpha reductase in the skin, which enhances sebaceous activity.

• Skin Thickness, Collagen, and Elastin

The decline in estrogen levels during menopause leads to a reduction in collagen and elastin synthesis, essential proteins for skin firmness and elasticity. Although testosterone is not the primary hormone regulating these proteins, some studies suggest that testosterone therapy may partially counteract collagen loss and improve skin thickness. The proposed mechanism involves the conversion of testosterone into estrogens via the aromatase enzyme in skin tissues, which may stimulate collagen and elastin production.

• Wrinkle Depth

The reduction in collagen and elastin during menopause contributes to wrinkle formation and deepening. By potentially increasing the synthesis of these proteins, testosterone therapy may reduce wrinkle depth and improve overall skin appearance.

Comparing the Effects of Estradiol and Testosterone on Collagen Synthesis

Estradiol’s effect on collagen production is significantly stronger than that of testosterone. While estradiol directly activates the expression of collagen-related genes, testosterone has a less pronounced effect and largely depends on its conversion to estradiol via the aromatase enzyme in the skin. Comparative studies have shown that estradiol increases collagen production in postmenopausal skin by 48%, while testosterone has a modest effect, increasing synthesis by only 10-15% when administered in physiological doses (Shen et al., 2014).

The Role of Progesterone in Skin and Hair Health

Progesterone has a complementary role in hormonal balance and, as mentioned in previous discussions, is a vital hormone in the context of hormone replacement therapy (HRT). In this context, it plays an additional role in modulating the androgenic effects of testosterone by acting as an inhibitor of 5-alpha reductase, reducing the conversion of testosterone into DHT. This helps mitigate potential adverse effects on the scalp in predisposed women. Additionally, progesterone promotes skin hydration and may improve overall hair quality by preventing hair loss and maintaining proper hormonal balance.

Overall Impact of Hormone Replacement Therapy (HRT) on Skin and Hair

Clinical studies have evaluated the impact of HRT on the skin and have shown that estrogen treatment reduces wrinkle depth by 30% to 40% after one year of therapy (Sumino et al., 2004). This is associated with an increase in dermal collagen content and improved skin hydration.

Histological studies in postmenopausal women receiving HRT have shown a significant increase in Type III collagen, particularly in the first year of treatment, suggesting an improvement in skin elasticity and firmness (Sumino et al., 2004). Additionally, HRT has also been shown to reduce hair loss and improve hair thickness in women suffering from postmenopausal androgenetic alopecia.

BIBLIOGRAPHY

(1) Brincat, M., Baron, Y. M., & Galea, R. (2005). Estrogens and the skin. Climacteric, 8(2), 110-123. https://doi.org/10.1080/13697130500118195

(2) Thornton, M. J. (2013). Estrogens and aging skin. Dermato-endocrinology, 5(2), 264-270. https://doi.org/10.4161/derm.22805

(3) Sumino, H., Ichikawa, S., Abe, M., Endo, Y., Kumakura, H., Takayama, Y., … & Kurabayashi, M. (2004). Effects of hormone replacement therapy on skin composition and aging in postmenopausal women. Journal of Dermatological Science, 35(3), 191-198. https://doi.org/10.1016/j.jdermsci.2004.06.004

(4) Zouboulis, C. C. (2009). Androgens and the sebaceous gland. Dermatologic Therapy, 22(5), 288-294. https://doi.org/10.1111/j.1529-8019.2009.01245.x

(5) Bolke, L., Schlippe, G., Gerß, J., Voss, W. (2019). A collagen supplement improves hair growth and thickness in women suffering from temporary hair thinning. Journal of Cosmetic Dermatology, 18(6), 1501-1508. https://doi.org/10.1111/jocd.12930

(6) Shen, W., Wong, T., Cheng, S. (2014). Effects of estrogen and testosterone on collagen metabolism in dermal fibroblasts. Journal of Investigative Dermatology, 134(2), 403-410. https://doi.org/10.1038/jid.2013.345

La entrada Research has demonstrated that estrogen therapy can increase collagen production in postmenopausal skin by approximately 48% after six months of treatment. se publicó primero en Neolife.

In a clinical trial in women aged 45 to 60, 120 mg/day of hyaluronic acid significantly improved dermal hydration and elasticity after 12 weeks compared to the placebo group.

The deterioration of Skin and joints share the progressive loss of collagen, elastin, and hyaluronic acid in our tissues. These substances not only provide support and elasticity to the skin, but are also essential for maintaining the function of our joints.

Dr. Alfonso Galán – Neolife Medical Team

One of the most promising strategies, with the strongest scientific backing, is oral hyaluronic acid supplementation, both for skin care and for joint health.

As we age, two of the most frequent complaints among men and women are the appearance of wrinkles, loss of firmness and radiance in the skin, and the onset of joint discomfort, stiffness, or even the first signs of osteoarthritis.

Although these processes are natural, they share a structural cause: the gradual decline of collagen, elastin, and hyaluronic acid in our tissues. These substances not only provide support and elasticity to the skin, but are also essential for maintaining the cushioning function of our joints.

The good news is that today we know we can act from within, with safe and effective interventions that help reverse or slow down these changes.

One of the most promising and best-supported interventions is oral hyaluronic acid supplementation, both for skin care and joint health.

Skin hydration and firmness from within

As we age, the hyaluronic acid (HA) content in our skin decreases dramatically. This contributes to loss of volume, elasticity, and firmness, and to the formation of wrinkles.

Double-blind, placebo-controlled clinical studies have shown that oral hyaluronic acid supplementation:

• Significantly increases dermal hydration (up to +28% in 6–12 weeks)
• Reduces wrinkle depth by 10% to 20%
• Improves skin elasticity and overall texture
• Enhances fibroblast activity, stimulating the production of collagen and elastin

In a clinical trial in women aged 45 to 60, 120 mg/day of hyaluronic acid significantly improved dermal hydration and elasticity after 12 weeks compared to placebo.

Protected joints, restored movement

Hyaluronic acid is also a natural component of synovial fluid and joint cartilage, where it acts as a “natural lubricant.”

In patients with mild to moderate osteoarthritis, multiple clinical trials have shown that oral hyaluronic acid:

• Reduces joint pain (significant improvements on the WOMAC scale of osteoarthritis-related disability)
• Improves mobility and joint function
• Increases collagen and proteoglycan content in cartilage
• Reduces the need for anti-inflammatory medications in chronic joint degeneration

Effective doses used in studies range between 80 and 200 mg daily, with visible improvements in 8–12 weeks.

How does oral hyaluronic acid work?

Although for many years it was thought that hyaluronic acid had to be injected to be effective, we now know that:

• Oral hyaluronic acid is broken down in the intestine into bioactive units.
• These units are absorbed and stimulate CD44 receptors, inducing the synthesis of more endogenous hyaluronic acid and collagen.
• Increases in hyaluronic acid content in the dermis and cartilage have been documented after oral supplementation.

Powerful synergies

At Neolife, we recommend combining hyaluronic acid with other active ingredients that reinforce its action.

This combination has shown greater clinical and functional efficacy in studies than hyaluronic acid alone.

Moreover, as we discussed in another article on our blog, it has a wonderful synergy with Hormone Optimization Therapy.

What do the studies say?

Recent systematic reviews and meta-analyses conclude that:

• Oral hyaluronic acid increases skin hydration and elasticity compared to placebo.
• Reduces joint pain in knee and hand osteoarthritis.
• Improves quality of life and function in active older adults.
• Shows excellent tolerance and safety in the medium and long term.

Conclusion

Science supports the use of oral hyaluronic acid as an effective and safe intervention for:

• Care for your skin from within
• Prevent and improve joint wear
• Maintain functional youth for longer

Just one capsule a day can make a meaningful difference in your skin and joint health.

BIBLIOGRAPHY

(1) Fukui T, et al. The effect of hyaluronic acid ingestion on dry skin: a double-blind, placebo-controlled study. Clin Cosmet Investig Dermatol. 2017;10:267–273.

(2) Kalman DS, et al. Effect of a natural extract of chicken combs with a high content of hyaluronic acid on pain relief and quality of life in subjects with knee osteoarthritis. Nutr J. 2008;7:3.

(3) Oe M, et al. Oral hyaluronan relieves knee pain: A review. 2021;13(1):223.

(4) Sato H, et al. Clinical effects of hyaluronic acid on dry skin. J New Rem Clin. 2002;51:548–556.

(5) DuRaine GD, et al. Evaluation of oral hyaluronan for osteoarthritis symptom relief: A meta-analysis. Int J Rheum Dis. 2020;23(5):560–568.

La entrada The power of oral hyaluronic acid: hydration, youthfulness, and mobility from within se publicó primero en Neolife.

The combination of bioidentical estradiol and micronized progesterone has shown, according to scientific literature, no association with thrombotic events or an increased risk of breast cancer.

The warnings about hormone replacement therapy (HRT) date back to 2002, when the Women’s Health Initiative (WHI) study linked the combined therapy CEE + MPA (Conjugated Equine Estrogens + Medroxyprogesterone Acetate) to an increased risk of breast cancer and cardiovascular events.

Dr. Alfonso Galán – Neolife Medical Team

Women suffering from debilitating symptoms were kept away from an effective treatment due to unfounded fears, losing quality of life as well as bone and vascular protection.

In July 2025, the U.S. Food and Drug Administration (FDA) convened a panel of experts to reevaluate the evidence surrounding Hormone Replacement Therapy (HRT) in menopausal women. This marks a turning point in the institutional narrative that, for decades, has been dominated by fear, black box warnings, and a distorted perception of risk.

At Neolife, we welcome this step as an act of scientific and medical justice — but also as a reminder of the great harm that misinformation about HRT has caused. In this article, we analyze in depth the panel’s conclusions, the key studies discussed, and, above all, the fact that the formulations we use at Neolife (bioidentical estradiol and micronized progesterone) have shown no increase in cardiovascular or cancer risk.

What Was Said at the FDA Panel?

1. Removal of the most severe warnings (black box warnings) for certain forms of HRT.
2. Recognition of previously minimized benefits: cardiovascular protection, improved bone health, reduction of hot flashes, and enhanced mood—especially in women under 60 or within the first 10 years after menopause.
3. Lack of differentiation between formulations: one major criticism was the failure to distinguish between treatments using conjugated equine estrogens (CEE) and medroxyprogesterone (MPA), versus bioidentical options.

The Legacy of the WHI and Its Consequences

The warnings about HRT trace back to 2002, when the Women’s Health Initiative linked CEE + MPA to an increased risk of breast cancer and cardiovascular events. However, in the years since, it has become clear that:

• The observed risk does not apply to all formulations or all women.
• The late age of treatment initiation (average age in WHI: 63 years) distorted the outcomes.
• The study did not use bioidentical estrogens or micronized progesterone.

As a result, millions of women gave up a beneficial therapy based on fears that we now consider unfounded for many patients.

Current Evidence: What Does Science Say About Bioidentical HRT?

Studies such as E3N (France) have demonstrated that oral bioidentical estradiol combined with micronized progesterone does not increase breast cancer risk (RR: 0.9).

A meta-analysis (Scarabin, 2018) confirms that the safest combination is transdermal estradiol plus micronized progesterone, with no significant increase in thromboembolic risk.

Differences between formulations

The Neolife Approach: Evidence, Personalization, and Safety

At Neolife, we use HRT in a personalized and evidence-based manner, with:

• Bioidentical estradiol
• Micronized progesterone
• Regular clinical and laboratory monitoring

This combination has consistently shown no association with thrombotic events or increased breast cancer risk in the short- to medium-term scientific literature.

What Happens Next?

If the FDA is now willing to reconsider its most severe warnings based on current evidence, the next logical step would be to retract and acknowledge the harm caused over the past two decades.
Women with debilitating symptoms were denied an effective treatment due to misplaced fears, losing not only quality of life but also bone and vascular protection.

Medicine must have the courage to correct its course. Today, we know that well-prescribed, bioidentical, and personalized HRT is a powerful, effective, and safe tool for many women.

Conclusion

The FDA panel marks a shift in direction, but there is still a long road ahead — many physicians and patients remain to be educated. At Neolife, we have long applied an evidence-based approach, free from dogma and with safety as our top priority. It is time to rewrite the narrative of HRT — with science, prudence, and respect for women’s health.

BIBLIOGRAPHY

(1) Scarabin, P. Y. (2018). Progestogens and venous thromboembolism in menopausal women: an updated oral versus transdermal estrogen meta-analysis. Climacteric, 21(4), 341–345.

(2) Fournier, A. et al. (2008). Use of different postmenopausal hormone therapies and risk of histology- and hormone receptor-defined invasive breast cancer. Journal of Clinical Oncology, 26(8), 1260–1268.
(E3N cohort, Francia)

(3) Manson, J. E. et al. (2013). Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA, 310(13), 1353–1368.

(4) The NAMS 2022 Hormone Therapy Position Statement Advisory Panel. (2022). The 2022 Hormone Therapy Position Statement of The North American Menopause Society. Menopause, 29(7), 767–794.

(5) FDA Expert Panel on Menopause and Hormone Replacement Therapy (2025). U.S. Food & Drug Administration Public Meeting Archive: July 17, 2025.

La entrada The FDA Reconsiders Its Warnings on Hormone Therapy in Menopause: The Beginning of a New Era for Women’s Health? se publicó primero en Neolife.

Ashwagandha (Withania somnifera) is one of the most widely studied adaptogens in modern biomedical literature. Traditionally used in Ayurvedic medicine, its pharmacological profile has been extensively investigated over the past decade.

Ashwagandha acts as a neuroendocrine modulator. It helps to “re-educate” the Hypothalamic-Pituitary-Adrenal (HPA) axis, normalizing cortisol production and reducing disproportionate sympathetic activation.

Dr. Alfonso Galán – Neolife Medical Team

Why is chronic stress such a relevant issue today?

At Neolife, we increasingly observe a common pattern: patients who appear healthy but present symptoms related to persistent stress, poor nighttime rest, daytime fatigue, non-pathological anxiety, or low mood. Neuroinflammation, dysfunction of the HPA axis, sympathetic hyperactivity, and circadian rhythm disruption are common mechanisms underlying these symptoms.

Chronic stress continuously activates the HPA axis and leads to dysregulation of cortisol production. This can result in:

• Initial states of hypercortisolism followed by relative adrenal exhaustion.
• Sleep disorders and maintenance insomnia.
• Anticipatory anxiety and adjustment disorders.
• Functional immunosuppression.
• Thyroid imbalances (due to cortisol interference with T4-to-T3 conversion).
• Metabolic and appetite disturbances.

This is not just about “feeling stressed.” It is a real pathophysiological cascade that compromises both physical and mental health.

Ashwagandha: an adaptogen with solid scientific evidence

Ashwagandha Ashwagandha (Withania somnifera) is one of the most widely studied adaptogens in modern biomedical literature. Traditionally used in Ayurvedic medicine, its pharmacological profile has been extensively investigated over the past decade.

The most relevant and clinically demonstrated effects of ashwagandha include:

• Stress and cortisol reduction: a meta-analysis of 12 controlled clinical trials found that supplementation with ashwagandha significantly reduced serum cortisol levels in patients with chronic stress (Lopresti et al., 2022).
• Improved sleep: in a recent double-blind trial (Langade et al., 2019), ashwagandha significantly improved sleep quality (assessed by PSQI) and reduced sleep onset latency, even in people with mild to moderate insomnia.
• Mood improvement and anxiety reduction: several controlled studies have shown that ashwagandha supplementation can reduce anxiety scores (assessed by scales such as HARS or DASS-21) by 30–40% after 8 weeks, with effects similar to or greater than first-line anxiolytics—without their side effects.
• HPA axis regulation: ashwagandha acts as a neuroendocrine modulator. It helps to “re-educate” the HPA axis, normalizing cortisol production—both in hypercortisolism and in functional hypocortisolism—while reducing disproportionate sympathetic activation.
• Synergistic potential with melatonin and relaxing supplements: combined use with melatonin, GABA, L-theanine, saffron extracts, or passionflower has been shown to improve sleep quality, emotional well-being, and reduce dependency on hypnotics or antidepressants, often allowing for a controlled tapering.

Look for the Sensoril® extract

Sensoril® is a standardized, highly bioavailable extract of ashwagandha with an optimized withanolide concentration (≥10%) and strong support from clinical trials. Sensoril® combines root and leaf extracts, which differentiates it from other formulations focused only on the root (such as KSM-66®), providing greater antioxidant and anxiolytic potency.

Sensoril® has been shown to:

• Reduce cortisol by up to 24% in 60 days.
• Significantly improve energy and vitality.
• Decrease fatigue by 30–45%.
• Enhance cognitive performance and reduce distraction-related errors.

Who can benefit from the use of ashwagandha?

• Patients with mild to moderate anxiety.
• Sleep-onset or maintenance insomnia.
• Chronic occupational stress or burnout.
• Athletes with signs of adrenal fatigue.
• Mild reactive depression.
• Subclinical hypothyroidism with an inflammatory profile.
• Individuals tapering off anxiolytics/hypnotics.

Conclusion

Ashwagandha Ashwagandha represents an option with a solid scientific foundation to address one of the great health challenges of the 21st century: chronic stress and its multiple somatic and psycho-emotional manifestations that we see daily in clinical practice. Its efficacy in regulating the HPA axis, improving sleep quality, energy, and mood makes it an indispensable therapeutic tool in integrative health protocols such as those we develop at Neolife.

BIBLIOGRAPHY

(1) Lopresti AL, Smith SJ, Malvi H, Kodgule R. An investigation into the stress-relieving and pharmacological actions of an ashwagandha (Withania somnifera) extract: a randomized, double-blind, placebo-controlled study.
Medicine (Baltimore). 2019;98(37):e17186.

(2) Pratte MA, Nanavati KB, Young V, Morley CP. An alternative treatment for anxiety: a systematic review of human trial results with ashwagandha (Withania somnifera).
J Altern Complement Med. 2014;20(12):901-908.

(3) Langade D, Kanchi S, Salve J, Debnath K, Ambegaokar D. Clinical evaluation of the spermatogenic activity of the root extract of Ashwagandha (Withania somnifera) in oligospermic males: A pilot study.
Evid Based Complement Alternat Med. 2013;2013:571420.

(4) Chandrasekhar K, Kapoor J, Anishetty S. A prospective, randomized double-blind, placebo-controlled study of safety and efficacy of a high-concentration full-spectrum extract of ashwagandha root in reducing stress and anxiety in adults.
Indian J Psychol Med. 2012;34(3):255-262.

(5) Ng QX, Loke W, Venkatanarayanan N, Lim DY, Soh AY. A systematic review and meta-analysis of the clinical use of Withania somnifera (Ashwagandha) to improve sleep: current evidence and future directions.
J Ethnopharmacol. 2022;284:114787.

La entrada Ashwagandha: A natural and effective solution for stress, anxiety, and insomnia se publicó primero en Neolife.

The impact of testosterone on mood and mental health is also significant.

Men with low testosterone levels often experience symptoms such as fatigue, irritability, difficulty concentrating, and depression. Low testosterone is also a significant risk factor for cardiovascular diseases, including atherosclerosis.

Dr. Alfonso Galán – Neolife Medical Team

Testosterone levels typically peak between the ages of 20 and 30. From around age 30–35, levels begin to decline gradually at an approximate rate of 1% per year. This gradual decline, known as late-onset hypogonadism or “andropause,” can be accelerated by various factors.

Testosterone (T) is an essential hormone in the male body, playing a fundamental role not only in the development of secondary sexual characteristics but also in a wide range of functions affecting physical and mental health.

Although often associated with youth and vitality—and trivialized as a hormone that only enhances sexual performance or helps build muscle—maintaining healthy levels of free testosterone in older men can have deep and lasting benefits for overall health and quality of life. In the following lines, we’ll explain how testosterone influences areas such as cardiovascular health, mood, body composition, and more, as well as the factors that contribute to its age-related decline.

The Decline of Testosterone With Age

Testosterone levels typically reach their peak between the ages of 20 and 30. After 30–35, levels begin to gradually decrease at a rate of about 1% per year. This slow decline, referred to as late-onset hypogonadism or “andropause,” can be accelerated by factors such as chronic stress, obesity, physical inactivity, excessive alcohol intake, poor diet, and chronic diseases like type 2 diabetes.

Testosterone circulates in the blood in three main forms: bound to proteins such as sex hormone-binding globulin (SHBG), loosely bound to albumin—the most abundant protein in the body—and free. It is this free testosterone that is biologically active and available to the body’s tissues, and it is the primary metric we focus on in lab testing to assess the real status of our male patients. With age, not only do total testosterone levels decrease, but SHBG levels also increase, further reducing the free fraction, while the weaker bond with albumin only partially compensates for the loss of bioavailable testosterone.

Factors Affecting Testosterone Production With Age

In addition to natural aging, several factors can contribute to reduced testosterone production:

1. Chronic stress: Persistent stress raises cortisol levels, a hormone that inhibits testosterone production in the testes.
2. Obesity: Body fat, especially abdominal fat, converts testosterone into estrogen via the enzyme aromatase, lowering the availability of free testosterone.
3. Physical inactivity: Lack of exercise reduces stimulation for testosterone synthesis. Physical activity—especially strength training—is a powerful promoter of testosterone production.
4. Nutrient deficiencies: Minerals like zinc and magnesium, as well as vitamin D, are essential for testosterone synthesis. Deficiencies in these nutrients can limit hormone production.
5. Poor sleep quality: Testosterone is primarily produced during deep sleep. Inadequate rest can significantly reduce its levels.
6. Alcohol and tobacco consumption: Both negatively affect testicular function and testosterone production.

Here are some key strategies to optimize testosterone production: manage stress, engage in strength training, eat a nutritious diet, get adequate sleep, avoid smoking, and limit alcohol. It’s no coincidence that the absence of these good habits is linked to worse aging outcomes—testosterone is one of the mechanisms through which lifestyle profoundly impacts health.

Cardiovascular Benefits of Maintaining Optimal Testosterone Levels

The relationship between testosterone and cardiovascular health has been extensively researched. For many years, it was mistakenly believed that high testosterone levels increased cardiovascular risk. However, more recent studies have shown that low testosterone levels are, in fact, a significant risk factor for cardiovascular diseases, including atherosclerosis. Among these studies:

1. A meta-analysis published in The Journal of Clinical Endocrinology & Metabolism (2011) linked low testosterone levels to a higher risk of cardiovascular mortality.
2. A longitudinal study by Vikan et al. (2009) demonstrated an inverse relationship between free testosterone and the development of subclinical atherosclerosis.
3. Research by Shores et al. (2006), published in Archives of Internal Medicine, showed that testosterone replacement therapy (TRT) may reduce mortality in men with testosterone deficiency.
4. The “Testosterone Trials,” published in The New England Journal of Medicine (2016), involving over 700 older men with low testosterone, demonstrated significant improvements in bone density, anemia, and sexual function, without an increase in cardiovascular events.
5. A 2023 study in The Journal of the American College of Cardiology involving a large cohort showed that testosterone replacement therapy in men with hypogonadism was associated with a significant reduction in major cardiovascular events, such as heart attacks and strokes, reinforcing the safety and cardiovascular benefits of this intervention in selected populations.

Testosterone supports cardiovascular health by promoting vasodilation, improving blood flow, and reducing inflammation. It also helps regulate cholesterol levels by lowering LDL (“bad” cholesterol) and increasing HDL (“good” cholesterol). When testosterone levels are low, plaque buildup in arteries (atherosclerosis) increases, which can lead to heart attacks and strokes.

Moreover, TRT in testosterone-deficient men has been shown to significantly improve endothelial function, reduce arterial stiffness, and enhance overall cardiovascular health markers. This suggests that maintaining optimal testosterone levels is not only beneficial but crucial in preventing cardiovascular diseases in older men.

Testosterone and Emotional and Sexual Well-Being

Testosterone has a major impact on mood and mental health. Men with low levels often report fatigue, irritability, trouble concentrating, and depression. This is partly because testosterone affects the production of key neurotransmitters like serotonin and dopamine, which regulate mood and feelings of well-being.

Several studies have shown that testosterone replacement therapy can significantly improve depressive symptoms in men with hypogonadism.

For example, a study published in The Aging Male (2020) assessed 200 men treated with TRT and found significant improvements in depression, anxiety, and overall quality of life. Similarly, a randomized controlled trial published in The Journal of Clinical Psychiatry (2019) found that men with hypogonadism treated with TRT showed greater improvements in mood and general well-being compared to the placebo group. Adequate testosterone levels are also associated with increased confidence, motivation, and stress resilience. This positive effect on mood not only improves quality of life but also directly influences productivity, relationships, and—as we see in clinical practice daily—our patients’ ability to make lifestyle changes as they feel more driven and determined.

Testosterone also plays a critical role in sexual function, desire, and erection. This is far from frivolous, as a satisfying sex life adds years to our life and life to our years. Testosterone enhances libido by stimulating brain areas related to arousal, supports tissue elasticity—which improves both sexual performance and the appearance of the genitals—and increases blood flow to the genitals, enhancing erection quality. It also promotes erectile tissue health, improving responsiveness to stimulation. Adequate testosterone levels can even enhance the flaccid appearance of the penis by promoting better vascularization, making it appear fuller and better shaped.

Testosterone, Muscle, and Fat

Testosterone is essential for maintaining muscle mass and regulating body fat. It stimulates protein synthesis in muscles, promoting growth and recovery. At the same time, it helps mobilize fat stores by increasing insulin sensitivity and improving lipid metabolism.

As testosterone levels decline, men tend to lose muscle and gain fat, particularly around the abdomen. These changes in body composition not only affect appearance but also increase the risk of metabolic diseases such as type 2 diabetes. Studies have shown that TRT can reverse these effects, supporting fat loss and muscle gain—even in older men.

Conclusion

Maintaining healthy free testosterone levels in older men is neither a frivolity nor a luxury—it is a necessity for ensuring a long, healthy, and fulfilling life.

From preventing cardiovascular disease to enhancing mood, body composition, and overall quality of life, testosterone plays an integral role in male well-being.

With a combination of healthy lifestyle choices, regular exercise, a balanced diet, and—when necessary—medical interventions like TRT, it is possible to maintain optimal hormone levels well into old age. Prioritizing hormonal health not only helps prevent many aging-related conditions but also enables a more active and satisfying life.

BIBLIOGRAPHY

(1) Ohlsson, C., et al. (2011). Low testosterone levels are associated with increased mortality in men: a meta-analysis. The Journal of Clinical Endocrinology & Metabolism, 96(10), 3007-3019.

(2) Vikan, T., et al. (2009). Serum levels of testosterone and carotid atherosclerosis progression in men with and without cardiovascular disease. The 5th Tromsø Study, European Journal of Preventive Cardiology.

(3) Shores, M. M., et al. (2006). Testosterone treatment and mortality in men with low testosterone levels. Archives of Internal Medicine, 166(15), 1660-1665.

(4) Snyder, P. J., et al. (2016). Effects of Testosterone Treatment in Older Men. New England Journal of Medicine, 374(7), 611-624.

(5) Alexander, G. C., et al. (2023). Association Between Testosterone Replacement Therapy and Major Adverse Cardiovascular Events: A Large Cohort Study. The Journal of the American College of Cardiology, 81(1), 1-15.

(6) Zitzmann, M., et al. (2020). Effects of testosterone therapy on symptoms of depression in hypogonadal men: A longitudinal study. The Aging Male, 23(1), 1-7.

(7) McIntyre, R. S., et al. (2019). Testosterone augmentation in major depressive disorder: A randomized, double-blind, placebo-controlled trial. The Journal of Clinical Psychiatry, 80(5), e1-e8.

La entrada Testosterone: Much More Than a Simple Frivolity se publicó primero en Neolife.

Women with high progesterone levels during the luteal phase have up to a 30% lower risk of developing breast cancer compared to those with low levels.

Additionally,progesterone has calming and anxiolytic effects, mediated by its ability to modulate GABA receptors in the brain, which explains its role in improving sleep quality and reducing stress. It is also linked to more intense and satisfying orgasms.

Dr. Alfonso Galán – Neolife Medical Team

Women with balanced progesterone levels report greater relaxation and a better quality of life.

Progesterone is a vital steroid hormone that plays a crucial role in female physiology, particularly in the menstrual cycle, pregnancy, and reproductive health. However, its function is not limited to these aspects, as it also acts as a protective hormone in various organs and systems, contributing to disease prevention and overall well-being. Despite its importance in women, progesterone is not commonly used in men due to its effects on sexual function and male hormonal balance. Let’s delve deeper into all of this.

Physiological Functions of Progesterone in Women

Progesterone is mainly produced by the corpus luteum in the ovaries after ovulation and, in smaller amounts, by the adrenal glands and, during pregnancy, by the placenta. Its blood concentration varies throughout the menstrual cycle, peaking during the luteal phase. The luteal phase is the second half of the menstrual cycle, beginning after ovulation and ending with the onset of menstruation. During this phase, the ovarian follicle transforms into the corpus luteum, which produces progesterone. This hormone is essential for thickening and maintaining the endometrium (the innermost layer of the uterus), preparing it for the potential implantation of a fertilized egg. If pregnancy does not occur, the corpus luteum degenerates, causing progesterone levels to drop and leading to menstruation.

Below is a graph illustrating progesterone, estrogen, and other hormone levels throughout the menstrual cycle, along with changes in the endometrium and corpus luteum:

Among its physiological functions, the following stand out:

1. Regulation of the menstrual cycle: Progesterone prepares the endometrium for the implantation of a fertilized egg. If implantation does not occur, its levels drop, triggering menstruation.
2. Support of pregnancy: During gestation, progesterone maintains the endometrium and prevents premature uterine contractions.
3. Mammary gland development: Progesterone contributes to the development of mammary ducts and preparation for lactation.
4. Metabolic effects: Progesterone regulates glucose levels and plays a role in thermogenesis.

Progesterone and Endometrial and Breast Protection

One of the most relevant aspects of progesterone is its protective role in the endometrium and breasts. Adequate progesterone levels have been shown to reduce the risk of endometrial hyperplasia and endometrial cancer by counteracting the proliferative effect of estrogen.

In breast tissue, progesterone regulates cell proliferation, preventing excessive growth that could predispose individuals to breast cancer. Observational and clinical studies have shown that women with healthy progesterone levels have a lower incidence of breast cancer and reduced all-cause mortality.

A meta-analysis published in the Journal of Clinical Endocrinology & Metabolism indicated that women with high progesterone levels during the luteal phase have up to a 30% lower risk of developing breast cancer compared to those with low levels. Additionally, hormone therapies combined with natural progesterone have not shown the adverse event incidence observed in therapies using synthetic progestins.

Hormone Replacement Therapy and Progesterone

Hormone Replacement Therapy (HRT) is commonly used in postmenopausal women to relieve symptoms such as hot flashes, insomnia, and vaginal dryness. However, its effects go far beyond symptom relief. HRT has significant protective effects on bones, arteries, the heart, and the brain, reducing the risk of osteoporosis, cardiovascular diseases, and cognitive decline. The addition of progesterone to estrogen therapy is crucial for preventing endometrial hyperplasia. These protective effects make HRT an integral tool for well-being and disease prevention in postmenopausal women.

Numerous clinical studies have demonstrated that bioidentical progesterone—which is identical to the progesterone naturally produced by a woman’s body—is better tolerated and has a superior safety profile compared to synthetic progestins. Additionally, progesterone in HRT improves sleep quality, reduces anxiety, and contributes to an overall greater sense of well-being.

Calming Effects and Improved Sexual Health

Progesterone has calming and anxiolytic effects, mediated by its ability to modulate GABA receptors in the brain, explaining its role in improving sleep quality and reducing stress. Women with balanced progesterone levels report greater relaxation and a better quality of life.

In the sexual realm, progesterone plays an important role. It has been observed to contribute to better vaginal lubrication and increased sensitivity, which can enhance pleasure during sexual intercourse. Additionally, progesterone is linked to more intense and satisfying orgasms, thereby improving overall sexual health.

Progesterone in Men: Why Is It Not Used?

Despite its benefits in women, progesterone is not commonly used in men. This is because high progesterone levels can antagonize testosterone action, reducing libido and affecting erectile function.

There is some evidence that progesterone in men may have certain benefits in small amounts, such as reducing inflammation and supporting prostate health. However, excessive progesterone can lead to feminization symptoms, decreased sexual desire, and erectile dysfunction. Other studies have shown that progesterone administration in men can interfere with sperm production and reduce sexual responsiveness. This delicate balance is why progesterone is generally not used in men.

Conclusion

Progesterone is an essential hormone for women’s health, with functions that extend beyond reproduction. Its protective role in the endometrium and breast tissue makes it a key tool in cancer prevention and overall disease prevention. Additionally, its use in Hormone Replacement Therapy has been shown to improve quality of life, sexual health, and emotional well-being.

In men, however, its use is very limited and exceptional due to its adverse effects on sexual and hormonal function. Continued research in this field may provide new insights into the benefits and applications of progesterone in both sexes, but for now, its primary role remains in female health.

La entrada Progesterone: its importance in women and why we don’t use it in men se publicó primero en Neolife.

Maintaining optimal hormone levels, whether through a healthy lifestyle or interventions such as hormone replacement therapy, can play a fundamental role in slowing down biological aging.

Estradiol, progesterone, and testosterone act as key modulators of oxidative stress, inflammation, metabolism, and epigenetic mechanisms. These effects, collectively, help preserve telomere length and maintain a youthful epigenetic profile.

Dr. Alfonso Galán – Neolife Medical Team

Sex Hormones and Biological Aging

Biological aging is a multifaceted process involving molecular, cellular, and physiological changes. At Neolife, we often define it as the accumulation of cellular damage that prevents cells from functioning properly. As a result, the tissues and organs they form may also fail, potentially leading to disease and deterioration.

This level of accumulated damage is something we can measure. Two key parameters are commonly used and assessed daily in our consultations: One way to measure biological age is by evaluating telomere length, and the other is through epigenetic patterns, such as “epigenetic clocks.”

Sex hormones, including estradiol, progesterone, and testosterone, play a crucial role in regulating various physiological processes related to aging. Scientific evidence suggests that maintaining optimal levels of these hormones not only impacts overall well-being and health—as we have extensively discussed—but may also delay biological aging by influencing oxidative stress, metabolism, mood, and cellular repair mechanisms.

Estradiol and Biological Aging

Estradiol is a key estrogen in premenopausal women, known for its antioxidant and protective effects on various tissues. Studies have shown that estradiol:

1. Protects Against Oxidative Stress: Acts as a direct antioxidant by reducing free radicals and increasing the activity of antioxidant enzymes such as superoxide dismutase and glutathione peroxidase. This effect can protect telomeres from oxidation, preserving their length.
2. Modulates Epigenetic Mechanisms: Estradiol regulates gene expression through its interaction with nuclear receptors, positively affecting aging-related epigenetic markers, such as DNA methylation. More about this here.
3. Benefits the Cardiovascular System: Enhances vascular elasticity and reduces systemic inflammation, processes that indirectly impact telomere preservation and epigenetic stability.

Scientific Evidence:

• A study published in Menopause (2017) showed that postmenopausal women undergoing estrogen-based hormone replacement therapy (HRT) had significantly longer telomeres compared to those who did not receive HRT. In other words: younger biological ages.
• A longitudinal study in Nature Communications (2018) examined pre- and postmenopausal women, showing that those with higher estradiol levels had significantly longer telomeres.

Progesterone: A Regulator of Homeostasis and Aging

Beyond its reproductive role, progesterone (more about this here) acts as a modulator in the central nervous system and has anti-inflammatory and neuroprotective properties. Some of its key effects include:

1. Reducing Inflammation: Progesterone decreases the production of pro-inflammatory cytokines such as TNF-α and IL-6. Chronic inflammation is closely linked to telomere shortening and epigenetic aging.
2. Neuronal Protection: Studies in animal models have shown that progesterone can promote neuronal regeneration and protect against oxidative damage, contributing to cognitive health and slower brain aging.
3. Impact on Metabolism: Progesterone improves insulin sensitivity and regulates energy storage, critical factors for maintaining a healthy metabolism and, consequently, slowing biological aging.

Scientific Evidence: A study in Aging Cell (2020) highlighted that balanced progesterone levels are associated with youthful epigenetic profiles in postmenopausal women, emphasizing its importance in preserving epigenetic marks.

Testosterone: Beyond Masculinity

Testosterone, predominantly found in men but equally important in women, is crucial for bone, muscle, and metabolic health. Its effects on biological aging include:

1. Enhancing Metabolism: Testosterone increases muscle mass and reduces body fat, promoting greater insulin sensitivity and lower metabolic stress.
2. Protecting Against Oxidative Stress: By regulating the expression of antioxidant genes, testosterone helps reduce oxidative damage in cells and tissues.
3. Influencing Mood and Habits: Testosterone is linked to higher energy levels, motivation, and positive mood, which facilitates the adoption of healthy habits such as regular exercise and a balanced diet. These habits, in turn, positively impact telomeres and the epigenome. These lines are much more important than you may think. Your habits greatly impact your biological age and having your optimal Testosterone levels will make your will and drive greater and implementing good habits will be much easier and you will see the rewards of it much more…and sooner.

Scientific Evidence:

• A meta-analysis in the Journal of Clinical Endocrinology & Metabolism (2019) found that men with optimal testosterone levels had longer telomeres and lower aging-associated DNA methylation in key genes compared to those with hormone deficiency.
• A study published in Cell Reports (2021) highlighted how testosterone modulated epigenetic marks associated with aging, delaying the “epigenetic clock.”

Estrogen and Progesterone in Synergy

The balance between these two hormones is vital for successful and safe hormone replacement therapy. Their interaction is also crucial for healthy aging. For example:

• Antioxidant Synergy: Estradiol and progesterone together enhance antioxidant activity and reduce inflammation, promoting a more stable cellular environment.
• Impact on Telomere Length: In postmenopausal women, combined estrogen and progesterone therapy has been shown to prevent telomere shortening and maintain a youthful epigenetic profile.
• Neuroprotection: Both hormones contribute to brain health, reducing the risk of age-related neurodegenerative diseases.

Scientific evidence: An analysis in JAMA (2022) showed that combined estradiol and progesterone therapies in women not only improved cardiovascular and bone health, but also positively impacted molecular markers of aging.

Influence of Hormone Levels on Healthy Habits

Optimal sex hormone levels not only directly impact cellular mechanisms but also facilitate the adoption of healthy habits:

1. Energy and Exercise: Healthy levels of testosterone and estradiol improve vitality and the willingness to engage in physical activity, a key factor for metabolic health and cellular longevity.
2. Mood and Stress Management: Sex hormones modulate neurotransmitters such as serotonin and dopamine, improving mood and reducing chronic stress. This, in turn, protects telomeres and the epigenome.
3. Weight Control: Proper hormonal balance promotes efficient metabolism, reducing the risk of obesity, a factor that accelerates biological aging.

Molecular Mechanisms: Telomeres and Epigenome

Telomere Length:

Telomeres, the repetitive DNA regions at the ends of chromosomes, shorten with each cell division. However, oxidative stress and inflammation accelerate this process. Sex hormones influence:

• • Telomere Protection: By reducing oxidative stress, sex hormones directly protect telomere length.
  • Telomerase Activation: Some studies suggest that estradiol can stimulate telomerase activity, the enzyme responsible for lengthening telomeres.

Epigenetic Modifications:

DNA Methylation: Adequate hormone levels are associated with a more youthful DNA methylation profile in key genes.

• Metilación del ADN: Niveles adecuados de hormonas están asociados con un perfil de metilación más juvenil en genes clave.
• Transcriptional Regulation: Sex hormones activate or silence genes related to inflammation, oxidative stress, and DNA repair.

Conclusions

Maintaining optimal hormone levels, whether through a healthy lifestyle or interventions such as hormone replacement therapy, can play a critical role in slowing biological aging.

Estradiol, progesterone, and testosterone act as key modulators of oxidative stress, inflammation, metabolism, and epigenetic mechanisms, collectively preserving telomere length and maintaining a youthful epigenetic profile.

Research in this field continues to advance, highlighting the importance of sex hormones in promoting health and longevity.

BIBLIOGRAPHY

(1) Barrett, E. S., & Swan, S. H. (2015). Stress and androgen activity during fetal development. Endocrinology, 156(10), 3435-3441. https://doi.org/10.1210/en.2015-1262

(2) Kyo, S., Takakura, M., Kanaya, T., Zhuo, W., Fujimoto, K., Nishio, Y., & Inoue, M. (1999). Estrogen activates telomerase. Cancer Research, 59(23), 5917-5921.

(3) Horvath, S. (2013). DNA methylation age of human tissues and cell types. Genome Biology, 14(10), R115. https://doi.org/10.1186/gb-2013-14-10-r115

(4) Stanczyk, F. Z., Chaikittisilpa, S., & Mishell, D. R. (2014). Hormones and aging: Clinical aspects of hormone replacement therapy. Endocrinology and Metabolism Clinics of North America, 43(4), 867-878. https://doi.org/10.1016/j.ecl.2014.08.001

(5) Mousavi, S. A., Jasemi, M., Mousavi, S. A., & Naghizadeh, M. M. (2020). The effect of testosterone replacement therapy on telomere length: A systematic review and meta-analysis. Journal of Clinical Endocrinology & Metabolism, 105(3), 781-789. https://doi.org/10.1210/clinem/dgz211

La entrada Relationship Between Sex Hormones and Biological AgeRelación entre hormonas sexuales y edad biológica se publicó primero en Neolife.

Following a comprehensive review, Campbell et al. concluded that, regardless of its therapeutic efficacy as an antidiabetic drug, the use of metformin results in a reduction in all-cause mortality, including cancer and cardiovascular disease.

Dr. Alfonso Galán González – Neolife Medical Team

Metformin and Microbiota 

Metformin also alters our microbiota – the bacteria that live with us in symbiosis in our gut – and this action is a determining factor in both its positive hypoglycemic and “anti-aging” effects. 

The numerous health benefits associated with the use of metformin in treating patients with type 2 diabetes (DM2), together with data from preclinical animal studies, such as in the worm (nematode) C. Elegans and in mice, have prompted research into whether metformin also has effects as an anti-aging drug capable of increasing our longevity. In fact, several clinical trials such as MILES (Metformin In Longevity Study) and TAME (Targeting Aging with Metformin) have been designed to evaluate these potential benefits of metformin as an anti-aging drug and to overcome the doubts that the current evidence raises. 

In this blog post, we would like to explain in a simple way what we know today about its influence on the state of health and longevity in humans and other species and the mechanisms proposed for these actions.

Metformin

Metformin is an antidiabetic drug, specifically a synthetic biguanide, which is used orally and improves insulin sensitivity. It is a first-line hypoglycemic drug for the treatment of type 2 diabetes mellitus (DM2). Metformin was first synthesized in 1922 when the purported medicinal properties of a plant, the French lilac () were investigated. Metformin was introduced to treat DM2 in France in 1958, and today, more than 60 years later, it is still used daily by some 150 million people worldwide. 

It is an inexpensive, safe drug (the main adverse effect, which occurs in 20-30% of patients, is intestinal discomfort)… and it is effective. 

The use of metformin leads to weight loss in many patients and lowers HbA1c (glycated hemoglobin or glycosylated hemoglobin, a fundamental marker for monitoring DM2, and which indicates the evolution of our blood sugar levels in the last 2-3 months).  

Its use was strongly supported by the publication in 1998 of the UKPDS study, a 20-year prospective, randomized, multicenter study of patients with DM2 on metformin, which reported cardiovascular benefits of its use.  

Because metformin is so widely used, there is an opportunity to determine whether metformin has anti-aging properties.  

And what do we call anti-aging? We could say, and we hope you agree with us on this definition, that something has an anti-aging effect if it positively affects the duration of health, the period of life spent in good health and free of crippling diseases.

In this blog post, we are going to summarize what is typically very complex information, which might help us answer, …or not, the question of whether metformin has other positive effects on the aging process, in addition to its effects as a hypoglycemic agent.  

The presumed relationship between metformin and aging

Based on a systematic review of 53 studies, with a total population of more than 400,000 people, Campbell et al. concluded that, regardless of its therapeutic efficacy as an antidiabetic drug, the use of metformin results in a reduction in all-cause mortality, including cancer and cardiovascular disease2. This seems like a very interesting starting point in the investigation of the properties of a drug, doesn’t it? 

AMPK and mTOR

Metformin appears to act on the AMPK and mTOR metabolic pathways (which we have described extensively here). Specifically, it activates the AMPK pathway and inhibits signaling through the mTOR pathway. This mTOR pathway has important functions in the regulation of cellular metabolism, including nutrient signaling and IGF-1 (Insulin-like growth factor 1) mediated growth. Signaling through mTOR is associated with accelerated aging, and dysregulation of mTOR signaling is also associated with cancer progression, inflammatory and neurological diseases, as well as DM2.  

AMPK functions as an energy sensor that coordinates multiple signals related to energy production and the control of glucose and lipid metabolism. 

It is worth noting that AMPK sensitivity decreases with age, which furthers the argument that AMPK activators, such as metformin, may delay aging. 

Microbiota

Studies conducted on worms (C. Elegans) and mice, indicate that adding metformin to the diet may delay aging and increase the life expectancy of these beings. 

However, we also know that in these studies with C. Elegans, very high concentrations of metformin were used, which would be equivalent to about 5 kg of metformin daily for a human being. For an idea of magnitude here, the usual doses for treating type 2 diabetes (DM2) are between 850 mg and 2 g/day. 

Such doses in humans would be fatal, and the same would be expected for the C. Elegans, but in them, it appears that the toxicity is offset by the effects of metformin on the microbiota and inhibition of bacterial folate metabolism. 

These same effects have, of course, been investigated in humans. And indeed, metformin also alters our microbiota – the bacteria that live with us in symbiosis in our gut – and this action is a determining factor in both its positive hypoglycemic and “anti-aging” effects, as well as in its negative gastrointestinal adverse effects. In fact, metformin is only absorbed, it has a bioavailability of 50%, with half of what we ingest being eliminated with our bowel movements. 

Metformin, in another action that occurs in the intestine, elevates the release of GLP-1 or incretins. Incretins are part of an endogenous system involved in the physiological regulation of blood sugar. They increase insulin release in the presence of glucose, decrease glucagon release (a hyperglycemic hormone), and regulate appetite. 

This effect of metformin on the intestine is likely to be significant, so much so that metformin does not work by any route apart from orally. 

GDF15 

We also now know that metformin raises levels of something called GDF15 (Growth/differentiation factor-15) involved in weight loss and positive cardiovascular effects. In fact, in a study based on a proteomic analysis of plasma from 240 healthy, disease-free humans in the age range of 22 to 93, GDF15 was identified as the protein that correlates most positively with chronological age and is also known to reduce appetite. 

Mitochondria

Metformin seems to play an important role in the regulation of mitochondrial function and to exert a kind of quality control. It helps to eliminate damaged mitochondria and enhance mitophagy, a special form of autophagy that recycles poorly functioning mitochondria. The mitochondrion, as we may recall, is at the very core of aging, as we reported here.

Endothelial function

The endothelium (the innermost layer of our arteries) plays a fundamental role in the regulation of vascular function and is a source of a molecule like nitric oxide (NO), a vasodilator and signaling agent. Endothelial dysfunction is an early marker of cardiovascular disease. 

If we ask ourselves whether metformin can have a direct anti-aging effect on the endothelium, the answer based on clinical and preclinical data should be a clear YES, although it is true that the clinical data on this effect are difficult to separate from its effect on lowering blood sugar and improving insulin sensitivity.

Metformin directly protects the endothelium from hyperglycemia-induced dysfunction and premature senescence. 

Therefore, if it protects us from the progression of vascular diseases, we can safely say that it increases our disease-free life expectancy. 

Inflammation

Inflammation is related to all diseases associated with aging, and the aging process itself involves an inflammatory state that has come to be called Inflammaging. Several elemental studies using different cell types have reported that metformin inhibits the activation of the NF-kß inflammatory signaling pathway and downregulates the production of proinflammatory cytokines and genes that encode for the inflammatory response.

Autophagy

Autophagy is a necessary process for getting rid of damaged proteins and organelles at the cellular level and plays an important role in the regulation of cellular aging. We know that calorie restriction, which is quite popular right now, is a powerful inducer of autophagy. 

There appears to be a relationship between autophagy and metformin, but it is not clear that it can occur at the doses we would use in humans. 

Cancer

Diabetes has been associated with a higher risk of developing several types of cancer, and a retrospective study published in 2005 reported that type 2 diabetic patients treated with metformin had a lower risk of developing cancer and pointed to a possible link between metformin and the tumor suppressor LKB13. Its effect on the AMPK pathway has also been linked to its antiproliferative effects. 

The truth is that there is quite a bit of literature supporting these effects…but not all of them. 

And so, further studies, which are ongoing, are needed to prove this important link and whether it is due to metformin or simply secondary to its effects as a hypoglycemic, insulin sensitizer, or its inhibition of the mTOR pathway.

Neurological function

Diabetes causes hyperglycemia and hyperinsulinemia, and increases oxidative stress, vascular disease, and inflammation…and yes, all of these things are linked to cognitive impairment. 

There is pretty solid evidence that links the use of metformin in type 2 diabetics with cognitive improvements. The search for the precise molecular mechanism that mediates it is underway. 

Exercise

This is where we wish to place the focus of this article. 

Exercise activates AMPK, which in turn increases glucose uptake in muscles and improves insulin sensitivity, helping to offset the negative effects of obesity, diabetes, and cardiovascular disease, thereby reducing morbidity and improving health. And metformin, as we have mentioned above, has incredible effects on our health. 

Therefore, given that both exercise and metformin can improve glycemic control and that both mediate their effects through the activation of AMPK, if we combine the two, we should have an additive effect, right? 

Unfortunately, that does not appear to be the case. 

A prospective, double-blind, randomized, and controlled study in which men and women with prediabetes were put on an exercise regime for 12 weeks with placebo and metformin, or placebo only, or metformin only, reported the following results:

Both metformin and exercise improved skeletal muscle insulin sensitivity by 55% and 90%, respectively, but the combination resulted in only a 30% improvement.  

The results were similar for the effects on systolic blood pressure and C-reactive protein (CRP) -a marker of inflammation- which were reduced by 7 to 8% with metformin and exercise versus 20 and 25%, respectively, which were lowered separately. Additionally, metformin attenuated the exercise-induced increase in VO2max4. 

Additional questions about the benefits of combining metformin and exercise come from two studies with older adults. Konopka et al. reported that metformin (2000 or 1500 mg/day for those who experienced gastrointestinal discomfort) attenuated exercise-induced increases in insulin sensitivity and also reduced exercise-induced increases in mitochondrial respiration5.  

In the MASTERS (Metformin to Augment Strength Training Effective Response in Seniors) study, metformin, despite an increase in AMPK signaling, slowed the strength exercise-induced muscle hypertrophy response in healthy men and women over 65 years of age who participated in a supervised progressive resistance exercise training program for 14 weeks after a 2-week metformin treatment (1700 mg/day or placebo)6. 

And so, in view of these results, all the positive effects of metformin that we are enumerating could be overshadowed by apparently minimizing the positive adaptations that the anti-aging and pro-health measure par excellence, exercise, has on our bodies. 

Ongoing studies

There are mainly two ongoing studies that will give us that answer as to whether we may consider metformin an anti-aging drug. 

The Metformin in Longevity Study (MILES) is a double-blind study in which subjects act as their own placebo control group. It began in October 2014 and was conducted in 14 elderly participants with glucose intolerance to determine whether metformin (1700 mg/day) can cause physiological and transcriptomic changes in muscle and adipose tissue after 6 weeks of treatment. It also determined which pathways are affected by metformin and outlined possible molecular intermediates involved in metformin’s action mechanism. 

We already have data on the results of this study, although the conclusions have not been published. Preliminary analysis of the MILES results indicates that metformin can indeed induce anti-aging transcriptional changes in the tissues studied. 

The Targeting Aging with Metformin (TAME) study is a multicenter, double-blind, placebo-controlled trial that is planned to involve 14 research centers in the US and will enroll 3000 non-diabetic individuals aged 65 to 80 who will receive 1700 mg of metformin daily for 6 years. Follow-up will be at 3.5 years. 

Its objectives are: 

1. Clinical outcomes, measured as the occurrence of new age-related chronic diseases
2. Functional outcomes, such as changes in mobility
3. Biomarkers of the aging process such as inflammation and senescence  

After all this being said, as you can see, the jury is still out on whether we may consider metformin an anti-aging drug. The final results of these studies may give us the definitive verdict. We also need to know if the above mentioned study regarding exercise + metformin is really so, as it would be an almost insurmountable obstacle for its consideration as an anti-aging therapy.

BIBLIOGRAPHY

(1) Mohammed I, Hollenberg MD, Ding H, Triggle CR. A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan. Front Endocrinol (Lausanne). 2021 Aug 5;12:718942. doi: 10.3389/fendo.2021.718942. PMID: 34421827; PMCID: PMC8374068.


(2) Campbell JM, Bellman SM, Stephenson MD, Lisy K. Metformin Reduces All-Cause Mortality and Diseases of Ageing Independent of Its Effect on Diabetes Control: A Systematic Review and Meta-Analysis. Ageing Res Rev (2017) 40:31–44. doi: 10.1016/j.arr.2017.08.003  

(3) Evans JMM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and Reduced Risk of Cancer in Diabetic Patients. BMJ (2005) 330:1304–5. doi: 10.1136/bmj.38415.708634.F7 


(4) Malin SK, Braun B. Impact of Metformin on Exercise-Induced Metabolic Adaptations to Lower Type 2 Diabetes Risk. Exercise Sport Sci Rev (2016) 44:4–11. doi: 10.1249/JES.0000000000000070


(5) Konopka AR, Laurin JL, Schoenberg HM, Reid JJ, Castor WM, Wolff CA, et al. Metformin Inhibits Mitochondrial Adaptations to Aerobic Exercise Training in Older Adults. Aging Cell (2019) 18:e12880. doi: 10.1111/ acel.12880 

(6) Walton RG, Dungan CM, Long DE, Tuggle SC, Kosmac K, Peck BD, et al. Metformin Blunts Muscle Hypertrophy in Response to Progressive Resistance Exercise Training in Older Adults: A Randomized, Double- Blind, Placebo-Controlled, Multicenter Trial: The MASTERS Trial. Aging Cell (2019) 18:e13039. doi: 10.1111/acel.13039 

La entrada Metformin: An Anti-Aging Drug? se publicó primero en Neolife.

Current evidence supports a different, much more dynamic and discontinuous evolution of atheroma plaques.

Experimental and human observations support that recruitment of blood leukocytes mediated by activation of endothelial cells lining the arterial lumen is an early phenomenon in lesion formation.

Dr. Alfonso Galán González – Neolife Medical Team

Continuing with these articles on atherosclerosis, in this new installment, we will delve into how atherosclerotic lesions, plaques, are formed.  

Knowing how they are formed and what factors influence their evolution is essential to preventing their progression. 

Oxidized LDL and onset of lesions

Most reviews of the mechanisms of atherosclerosis postulate a pivotal role for oxidized LDL as the main driver of this disease. Two years ago, we wrote about this (here). But, despite a large body of evidence in this regard in animal studies, human studies confirming its causal role are not as numerous. Trials with antioxidant vitamins or a very effective lipophilic antioxidant have not reduced atherosclerotic events. Perhaps the answer lies in the observation that when oxidized lipids bind to plasminogen, they can activate fibrinolysis.. This means that oxidized lipids may promote atherogenesis, but also stimulate thrombolysis, an opposite effect that may contribute to this lack of net benefit in trials of antioxidant strategies.

Therefore, it is smart for us to look beyond the oxidation hypothesis for explanations of how LDL causes atherosclerosis.  

LDL aggregating in the intima, in association with proteoglycans or adaptive immune responses to native LDL, provide alternative mechanisms through which this lipoprotein promotes atherogenesis.  

Regardless of the initial trigger(s), experimental and human observations support that recruitment of blood leukocytes mediated by activation of endothelial cells lining the arterial lumen is an early phenomenon in lesion formation.

The resting endothelium resists the binding of blood leukocytes. However, in an atherogenic environment, endothelial cells can express leukocyte adhesion molecules that mediate the adhesion of white blood cells to the intimal surface. Chemical mediators direct the migration of adherent leukocytes into the arterial intima. Mononuclear phagocytes proliferate within the intimal layer (the site where the injury begins). These cells engulf lipids and become foam cells, the hallmark of atherosclerotic lesions. T-cells, the protagonists of the adaptive immune response, interact with cells of innate immunity within the intima.  

Cooperation between these cellular constituents of innate and adaptive immunity stimulates the production of proinflammatory cytokines that maintain and amplify the local inflammatory response.

In humans, the intima contains resident smooth muscle cells. Other smooth muscle cells (usually found in the media) can penetrate into the intima, where they join the resident smooth muscle cells to promote the accumulation of extracellular matrix that these cells synthesize within this expanding intimal layer.

Inexorability of atheroma progression 

Many have regarded atherosclerosis as an inevitable “degenerative” process that progresses continuously over time, but current evidence supports a much more dynamic and discontinuous evolution of atherosclerotic plaques. Episodes of systemic inflammation or regional inflammation away from the atherosclerotic plaque itself may provoke “crises” in plaque evolution and stimulate a round of inflammatory activation that may lead to cell migration, proliferation, lesion progression, and complication.

Arterial smooth muscle cells, which normally reside in the media layer of the artery, enter the intimal layer, where they can proliferate and undergo metaplasia to become macrophage-like cells. 

Atherosclerosis may not develop continuously, but rather in a way that alternates phases of relative inactivity with periods of rapid growth.  

Increasingly emerging evidence points to hematopoiesis (blood cell formation) as a key contributor to lesion evolution and as a link between regional inflammation, environmental stimuli, and atherogenesis..  

Mental stress, sleep disturbances, and injuries, or infections elsewhere in our body can stimulate hematopoiesis in bone marrow, supplying white blood cells that can populate the plaque. Also, extramedullary hematopoiesis, as well as the mobilization of already formed pools of white blood cells in the spleen, provide more white blood cells that can nest in our atheromatous plaques under stressful situations. 

In fact, the work that identified clonal hematopoiesis of indeterminate potential (also known as CHIP and explained in the previous article in this series on atherosclerosis) as a risk factor underscores the link between atherosclerosis and hematopoiesis. These observations have opened a window into the pathogenesis of atherosclerosis and provide a link between oncogenesis and atherogenesis that was unsuspected only a few years ago.  

The death of mononuclear phagocytes in the lesion, and their ineffective clearance (defective efferocytosis), promotes the formation of the lipid or necrotic core of the atherosclerotic lesion.

Lesion progression may occur silently over many decades. In fact, many young or middle-aged individuals have subclinical atherosclerotic lesions when we perform imaging tests..

“Vulnerable plaques” 

Acute episodes such as myocardial infarctions and ischemic strokes (Ictus) that complicate atherosclerosis arise from thrombosis or blood clot formation; a physical disruption of atherosclerotic plaques causes the most acute thromboses. 

The concept of “vulnerable plaque” has received considerable attention6. A fracture of the fibrous cap of the plaque (overlying the necrotic core) exposes the circulating blood and its clotting proteins to thrombogenic substances within the plaque, triggering acute thrombosis.  

The fibrous cap owes its tensile strength largely to interstitial collagen. Thinning of the fibrous cap arises from a decrease in collagen synthesis and an increase in its degradation associated with inflammation and overexpression of collagenases by inflammatory cells. Autopsy studies have implicated fibrous cap rupture as the cause of most fatal acute coronary syndromes. 

But these post-mortem studies don’t usually look at how many of these plaques with these characteristics are NOT causing acute thrombotic complications.  

Recent evidence has provided this missing information and has shown that plaques covered with this thin layer rarely cause clinical events, so perhaps the term “vulnerable plaque” is not the most appropriate term.  

In an era of intense lipid depletion, plaques of classic vulnerable morphology are in decline. Another mechanism of plaque disruption known as surface erosion appears to be on the rise and probably has a different pathophysiology. In this case, the triggering phenomenon of coronary obstruction does not involve fissure or rupture of the fibrous cap of the plaque, but rather a discontinuity in the endothelial lining of the intima. The application of an intravascular imaging technique known as optical coherence tomography allows the identification of plaque rupture and has led to the development of criteria for the diagnosis of probable or definite erosion in individuals with acute coronary syndromes. Erosion mechanisms involve endothelial injury, the participation of polymorphonuclear white blood cells, and neutrophil extracellular traps (NETs –see below–) as local contributors to thrombus formation and propagation.. 

To facilitate understanding, let’s summarize and graphically represent these two complications we may see in the plaque:  

In a, we see plaque rupture. This involves a fracture or fissure of the fibrous cap overlying the lipid core of the plaque. This physical alteration allows contact of blood clotting factors with thrombogenic material (mainly the potent procoagulant tissue factor) within the plaque. The resulting thrombosis can obstruct blood flow and cause cardiac ischemia. This mechanism explains approximately two-thirds of acute myocardial infarctions, but appears to be declining; current preventive therapies lead to a reduction in lipid accumulation within plaques and reinforcement of the fibrous cap.  

And in b, we observe what would be surface erosion. This cause of clot formation in the coronary arteries involves a kind of endothelial monolayer desquamation. Granulocytes trapped in the plaque or attached to the basement membrane of the intima may form neutrophil extracellular traps (NETs). NETs are a combination of nuclear DNA strands that have unwound, various neutrophil granular proteins and other proteins that bind from the blood, forming a kind of solid reactant on the surface of the intima that can spread inflammation and thrombosis.  

In the next (and final) installment of these articles on the current evidence on atherosclerosis, we will try to put all this together to make sense of it from a clinical point of view.

BIBLIOGRAPHY

(1) Leibundgut, G. et al. Oxidized phospholipids are present on plasminogen, affect fibrinolysis, and increase following acute myocardial infarction. J. Am. Coll. Cardiol. 59, 1426–1437 (2012). 

(2) Kubo, T. et al. The dynamic nature of coronary artery lesion morphology assessed by serial virtual histology intravascular ultrasound tissue characterization. J. Am. Coll. Cardiol. 55, 1590–1597 (2010). 

(3) Vergallo, R. & Crea, F. Atherosclerotic plaque healing. N. Engl. J. Med. 383, 846–857 (2020). 

(4) Schloss, M. J., Swirski, F. K. & Nahrendorf, M. Modifiable cardiovascular risk, hematopoiesis, and innate immunity. Circ. Res. 126, 1242–1259 (2020).

(5) Tuzcu, E. M. et al. High prevalence of coronary atherosclerosis in asymptomatic teenagers and young adults: evidence from intravascular ultrasound. Circulation 103, 2705–2710 (2001). 

(6) Waksman, R. et al. The lipid-rich plaque study of vulnerable plaques and vulnerable patients: study design and rationale. Am. Heart J. 192, 98–104 (2017).

(7) Libby, P. & Pasterkamp, G. Requiem for the ‘vulnerable plaque’. Eur. Heart J. 36,2984–2987 (2015). 

(8) Arbab-Zadeh, A. & Fuster, V. The myth of the “vulnerable plaque”: transitioning from a focus on individual lesions to atherosclerotic disease burden for coronary artery disease risk assessment. J. Am. Coll. Cardiol. 65, 846–855 (2015).

(9) Franck, G. et al. Haemodynamic stress-induced breaches of the arterial intima trigger inflammation and drive atherogenesis. Eur. Heart J. 40, 928–937 (2019).

La entrada The Current Landscape of Atherosclerosis Part 3 se publicó primero en Neolife.

How it works, and how what we eat and how we eat it influences our health

Low levels of fiber in the diet cause intestinal microorganisms to consume the mucus layer lining the intestine, which compromises the intestinal barrier function and leads to what is known as “leaky gut”. This may result in inappropriate activation of the intestinal immune system and may lead to metabolic endotoxemia.

Dr. Alfonso Galán González – Neolife Medical Team

The effect of the immune activation of the gut microbiota on the Brain-Gut-Microbiota Axis in obesity

Studies on mice that were fed a high-fat diet and very low in dietary fiber have shown long-term alterations in gut microbiota diversity, while high-fiber diets resulted in positive alterations in eating behavior, such as decreased food intake and increased satiety. Limited fiber intake resulted in a substantial reduction in microbiota diversity and abundance, which was largely reversible in a single generation when animals received a fiber-rich diet. However, continuation of the low-fiber diet for several generations resulted in a permanent loss of microbial diversity, which was not recoverable even with increased fiber supplementation (Sonnenburg et al.).

Low dietary fiber levels cause intestinal microorganisms, such as certain strains of Akkermansia muciniphila, to consume the mucin glycans in the mucus layer lining the intestine, compromising intestinal barrier function and leading to a condition known as “leaky gut”. Reduced intestinal barrier function may result in inappropriate activation of the intestinal immune system. When inflammatory mediators spread beyond the gut, systemic immune activation can occur, affecting multiple organs, including the brain, a state that has been termed metabolic endotoxemia (Cani et al.).

This state of metabolic endotoxemia has been shown to decrease central satiety mechanisms by influencing the secretion by enteroendocrine cells of satiating hormones such as PYY, cholecystokinin, and 5-HT, as well as reducing the expression of anorexigenic receptors in vagal afferents and in the hypothalamus.

This state of metabolic endotoxemia has been shown to decrease central satiety mechanisms by influencing the secretion by enteroendocrine cells of satiating hormones such as PYY, cholecystokinin, and 5-HT, as well as reducing the expression of anorexigenic receptors in vagal afferents and in the hypothalamus.

Circadian variations of BGM interactions

The time of day plays an important role in metabolism and energy processes, as well as in most physiological functions. Much of mammalian behavior and physiological functions are organized around circadian rhythms, including feeding behavior and digestive system activity, such as motility and secretory patterns. The suprachiasmatic nucleus (SCN), a small region of the brain located in the hypothalamus, is considered the “master clock”, responsible for pacing and synchronizing all circadian rhythms in mammals.  Disruption of the circadian rhythm may affect gastrointestinal function, the metabolism, and eating behaviors, and a considerable body of preclinical and clinical studies has demonstrated its association with an increased risk of chronic diseases, particularly metabolic syndrome, obesity, cardiovascular disease, and cancer.

In developed countries, the ubiquitous availability of food at all hours of the day, long-distance air travel across different time zones, and shift work have led to significant disruptions in circadian rhythms in terms of food intake. Specifically, the expansion of the window of time during which food is consumed, including late-night snacking, causes disturbances in the circadian rhythms of the Brain-Gut-Microbiota (BGM) interactions, which contributes to compromised metabolic function (Racz et al.).

The gut microbiota itself follows diurnal oscillations in composition and function and regulation is marked by the feeding rhythms of the host (Thaiss et al.). Therefore, the disruption of this balance between the timing of intake and circadian rhythms may lead to dysbiosis that may contribute to obesity and other metabolic dysfunctions.

Therapeutic implications

From what has been explained, it seems more than reasonable to use this evidence to develop strategies to combat obesity and provide better results than the usual ones based on modifying the macronutrient composition of the diet, which do not take into account the role of microbiota in developing resistance to weight loss.

Microbiota-targeted therapies

Microbiota-targeted therapies, such as treatment with novel probiotics or fecal microbiota transplantation (FMT), represent a new therapeutic option for obesity and metabolic syndrome. Small clinical studies have show good results.

Thus, in a small study of 18 individuals, where 9 received autologous FMT (from their own feces), and the other 9 received allogeneic FMT from a lean donor, and a second very similar study of 38 individuals, it was demonstrated that fecal microbiota transplantation from a lean donor increased butyrate-producing bacteria and improved insulin sensitivity in those recipients with metabolic syndrome (Vrieze et al.). However, the improved insulin sensitivity and associated changes in fecal microbiota were not maintained at 18 weeks of follow-up, due to the resilience of the recipient’s original microbiota.

Microbial products such as short-chain fatty acids (SCFA) are known to regulate feeding behavior in animal models through central mechanisms. For example, the consumption of a specific type of fiber that selectively increases propionate production by gut bacteria was correlated with a lower signaling of temptation and reward circuits in response to images of tasty food in 20 healthy non-obese men (Byrne et al.).

In order for these methods involving alterations in the gut microbiota to be sustained in the long term, dietary and behavioral changes need to be maintained over time so that the gut microbiota is fed with the nutrients necessary to continue the positive changes.

Temporary eating restrictions

Under the umbrella of the term intermittent fasting (IF), we have several forms of calorie restriction, such as alternate-day fasting and time-restricted eating.

Many recent studies have shown that metabolic pathways have diurnal rhythms. We believe that, under normal conditions, the cyclic expression of metabolic regulators coordinates a variety of cellular processes for more efficient metabolism.

The literature also shows us that IF may increase longevity, improve metabolic health, and help control hormonal changes, inflammatory reactions, lipid metabolism, and insulin sensitivity.

Time-restricted eating (TRE) is another proposed therapeutic approach to obesity and metabolic dysregulation that has gained significant attention in recent years (De Cabo et al.). TRE restricts food intake to a 6 to 8-hour window for a period of 24 hours with no calorie intake outside this window, as opposed to the 15 to 17- hour window of food intake that is common in Western countries.

The implementation of TRE where energy intake is limited to an 8-hour window prevents the harmful effects of metabolic diseases caused by high-fat and high-sugar diets without limiting daily calorie intake.

Based largely on studies in laboratory mice, it is hypothesized that time-restricted eating influences metabolic regulation through its effects on circadian rhythms, gut microbiota, and lifestyle.

In animals, TRE reduces fat accumulation and whole-body inflammation while improving glucose tolerance, reducing insulin resistance, and improving cholesterol control.

Allowing the digestive tract to have periods of time without food forces the body to burn fat during these periods instead of using energy from a continuous supply of glucose. In the absence of food intake, a metabolic shift occurs that forces the liver to produce ketone bodies from body fat when glucose is inaccessible. In addition to acting as fuel, ketone bodies are signaling molecules that have significant effects on multiple cellular and organ functions, including the brain.

It is believed that these systemic and cellular responses that are activated during fasting remain activated and strengthen mental and physical functioning, as well as resistance to disease even after resuming food intake.

Other potential factors that may contribute to the benefits of TRE include a subconscious reduction in snacking and overall calorie intake and changes in the gut microbial environment due to increased motility and secretion during the fasting period.

Despite impressive results in rodents, to date, the results of well-designed clinical trials to determine the effectiveness of this temporarily restricted food intake with or without calorie restriction in obese subjects with metabolic disturbances are, unfortunately, limited and inconsistent.

A study of overweight but otherwise healthy individuals who adhered to TRE significantly reduced their daily calorie intake primarily by eliminating alcohol and late-night snacking, resulting in sustained weight loss for up to one year (Gill et al.).

The randomized clinical trial TREAT, published in JAMA Internal Medicine in 2020, tested the effects of TRE on weight loss and other metabolic parameters in obese women and men (participants had a mean weight of 99.2 kg and a mean BMI of 32.7). The TRE group followed an eating schedule of 16: 8 hours and was instructed to eat whatever they wanted from 12 p.m. to 8 p.m. and to abstain completely from calorie intake from 8 p.m. to 12 p.m. the following day. The group with conventional meal timing (CMT) was instructed to eat three structured meals per day.

The investigators hypothesized that since TRE does not require a decrease in calorie intake in the 24-hour period, it must affect energy expenditure to achieve a negative calorie balance.

The primary outcome of TRE in the trial was significant weight loss in the TRE group and little to no change in weight in the CMT group. They also found a significant difference in appendicular lean mass index (in limbs) between the groups, but no change in other secondary outcomes such as fasting insulin, fasting glucose, or estimated calorie intake.

 The study concluded that, without other interventions, TRE is not necessarily more effective for weight loss than daytime eating and may cause loss of lean muscle mass (Lowe et al.); however, previous studies with time-restricted eating in overweight or obese humans showed a reduction in total calorie intake leading to a decrease in body weight and fat mass.

According to the results of the TREAT study, adherence to a regular physical exercise program and a healthy diet can prevent these unexpected side effects such as loss of lean mass.
More research in humans is needed to draw more definitive conclusions about TRE, but it seems that the way forward is to combine it with a healthy diet during the period of eating with good protein intake and associated with a regular physical exercise program to avoid loss of muscle mass.

BIBLIOGRAPHY

(1) Cani, P.D.; Amar, J.; Iglesias, M.A.; Poggi, M.; Knauf, C.; Bastelica, D.; Neyrinck, A.M.; Fava, F.; Tuohy, K.M.; Chabo, C.; et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007, 56, 1761–1772.

(2) Qin, Y.; Roberts, J.D.; Grimm, S.A.; Lih, F.B.; Deterding, L.J.; Li, R.; Chrysovergis, K.; Wade, P.A. An obesity-associated gut microbiome reprograms the intestinal epigenome and leads to altered colonic gene expression. Genome Biol. 2018, 19, 7.

(3) Racz, B.; Duskova, M.; Starka, L.; Hainer, V.; Kunesova, M. Links between the circadian rhythm, obesity and the microbiome. 
Physiol. Res. 2018, 67, S409–S420. 


(4) Thaiss, C.A.; Zeevi, D.; Levy, M.; Zilberman-Schapira, G.; Suez, J.; Tengeler, A.C.; Abramson, L.; Katz, M.N.; Korem, T.; Zmora, 
N.; et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell 2014, 159, 514–529. 


(5) Vrieze, A.; Van Nood, E.; Holleman, F.; Salojarvi, J.; Kootte, R.S.; Bartelsman, J.F.; Dallinga-Thie, G.M.; Ackermans, M.T.; Serlie, M.J.; Oozeer, R.; et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 2012, 143, 913–916e917

(6) Byrne, C.S.; Chambers, E.S.; Alhabeeb, H.; Chhina, N.; Morrison, D.J.; Preston, T.; Tedford, C.; Fitzpatrick, J.; Irani, C.; Busza, A.; et al. Increased colonic propionate reduces anticipatory reward responses in the human striatum to high-energy foods. Am. J. Clin. Nutr. 2016, 104, 5–14 


(7) de Cabo, R.; Mattson, M.P. Effects of Intermittent Fasting on Health, Aging, and Disease. N. Engl. J. Med. 2019, 381, 2541–2551. 


(8) Gill, S.; Panda, S. A Smartphone App Reveals Erratic Diurnal Eating Patterns in Humans that Can Be Modulated for Health 
Benefits. Cell Metab. 2015, 22, 789–798. 


(9) Lowe, D.A.; Wu, N.; Rohdin-Bibby, L.; Moore, A.H.; Kelly, N.; Liu, Y.E.; Philip, E.; Vittinghoff, E.; Heymsfield, S.B.; Olgin, J.E.; et al. Effects of Time-Restricted Eating on Weight Loss and Other Metabolic Parameters in Women and Men With Overweight and Obesity: The TREAT Randomized Clinical Trial. JAMA Intern. Med. 2020, 180, 1491–1499

(10) Sonnenburg, E.D.; Smits, S.A.; Tikhonov, M.; Higginbottom, S.K.; Wingreen, N.S.; Sonnenburg, J.L. Diet-induced extinctions in the gut microbiota compound over generations. Nature 2016, 529, 212–215 


La entrada The Role of the Brain-Gut-Microbiota Axis in Obesity (Part II) se publicó primero en Neolife.