Last week in part I of this series, we discussed How to Eat for Muscle Strength & Stamina as You Age-The 3 gram Leucine Rule. I explained that aging muscle does not lose its ability to grow, but it DOES becomes less sensitive to the usual anabolic signals—dietary protein, essential amino acids, insulin and resistance exercise. Today, in part II, I want to further explain anabolic resistance and how hormone imbalance, decline or excess, metabolic disease and chronic inflammation further weaken your muscle building response.
Sex hormones-estradiol and testosterone for women and testosterone for men, plus other hormones—cortisol, insulin, vitamin D, thyroid and more—are involved in muscle protein synthesis (MPS) in more ways than you may think. For example, estrogen and testosterone are considered anabolic hormones that drive muscle protein synthesis, reduce oxidative stress breaking down muscle with exercise, and help protect lean muscle mass. Other hormones present in excess as we get older or gain body fat—insulin and cortisol—serve to drive anabolic resistance and inhibit muscle protein synthesis. Vitamin D—technically a hormone, not a vitamin—at levels below about 50-60 actually contributes to insulin resistance and metabolic syndrome, both of which are driving factors for anabolic resistance leading to reduced muscle protein synthesis. These and other hormonal dysfunction or deficiencies definitely affect muscle growth and strength at any age, and become much more critical factors affecting our ability for muscle protein synthesis as we get older.
The good news is that most of the factors I am discussing can respond positively to the right medical treatments to restore hormone balance, and improve muscle protein synthesis when combined with adequate high-quality protein and complete essential amino acids, progressive resistance training, daily movement, metabolic health and quality of sleep. Together, these strategies help you successfully preserve muscle, strength, resilience, and independence as you age.
Anabolic Resistance: A Quick Overview
Muscle mass reflects the ongoing balance between muscle protein synthesis and muscle protein breakdown. Muscle protein synthesis builds and repairs muscle proteins leading to increase in muscle mass over time. Muscle protein breakdown dismantles damaged or unneeded proteins and releases amino acids to be recycled for reuse to build new healthy muscle.
Anabolic stimulus is the term used for any factor that stimulates the formation of lean body mass, or muscle tissue. The most important anabolic stimuli are 1) intake of protein, 2) intake of essential amino acids, 3) resistance exercise (strength or weight training), 3) certain hormones, particularly androgens in both men and women.
Anabolic resistance refers to the reduced ability of skeletal muscle to increase muscle protein synthesis after an anabolic stimulus, such as protein intake, essential amino acids, resistance exercise, or androgen therapy. This analogy helps make it clearer:
Anabolic Resistance means the doorbell still works. It is just quieter. You have to knock louder.
Reduced sensitivity to muscle building stimuli does not come from one defective pathway. It develops through several multiple inefficiencies that extend from digestion, impaired circulation, reduced amino-acid transport, alterations in intracellular signaling/hormonal influence, and loss or imbalance of critical hormonal drivers.
What are some causes of reduced delivery of protein to muscle?
Let’s dig into these causes in more detail:
- Splanchnic Extraction: Before muscle can use leucine and the other essential amino acids, the digestive system must absorb them, the bloodstream must transport them, and capillaries must deliver them to muscle fibers. It is common for older adults to experience having the intestines and liver retain a larger proportion of meal-derived amino acids (splanchnic extraction) making less available to reach skeletal muscle.
Insulin normally recruits small blood vessels within muscle after a meal, increasing microvascular perfusion and amino-acid delivery. Aging, inactivity, endothelial dysfunction and insulin resistance can weaken this response and so once again, there is less protein reaching the muscle to be used to build muscle fibers. Experiments have shown that improving muscle perfusion in older adults has substantially improved insulin-supported muscle protein synthesisand net muscle-protein balance.
- Growth switch signaling: Once leucine enters the muscle cell, amino-acid sensors—including Sestrin2 and leucyl-tRNA synthetase—help activate mechanistic target of rapamycin complex 1, or mTORC1. This signaling hub activates proteins such as S6 kinase 1 and 4E-BP1, which begin translating genetic instructions into new muscle proteins. Older muscle often shows a weaker mTORC1 response to a moderate amino-acid dose.
Paradoxically, parts of the pathway may remain somewhat activated at rest yet respond inadequately when protein arrives, much as chronically elevated insulin can coexist with reduced insulin responsiveness.
- Chronic Inflammation adds resistance: Chronic low-grade inflammation, oxidative stress and fat accumulation within and around muscle interfere with insulin–Akt–mTOR signaling. These conditions can also increase muscle break-down (catabolic) pathways, impair mitochondrial function and reduce muscle quality even when a body-composition test shows a relatively acceptable amount of lean mass. This helps explain why anabolic resistance varies greatly among people of the same age. A physically active, metabolically healthy 70-year-old may respond better to protein and training than a sedentary 55-year-old with visceral adiposity, diabetes, chronic inflammation and repeated periods of inactivity.
- Inactivity accelerates everything! Disuse represents one of the strongest causes of anabolic resistance. It is also the most easily reversible if you make different choices and decide to MOVE more! In older adults, only seven days of bed rest can blunt muscle protein response to essential amino acids, reduces mTORC1 signaling and lowers amino-acid transporter expression. And naturally, longer periods of inactivity produce even larger losses. Inactivity causes more insidious damage than just reducing muscle loading. It worsens insulin sensitivity, diminishes capillary perfusion, reduces mitochondrial function and impairs neuromuscular recruitment. ALL of these consequences of inactivity cause multiple muscle-loss pathways to occur simultaneously and even reinforce one another to further compound the problem.
Your biggest take home message today: Inactivity is devastating to muscles as we get older!
The protein foundation
In Part I we pointed out that older adults need a stronger and more consistent protein signal than younger adults. Expert groups commonly recommend at least 1.0–1.2 grams of protein per kilogram of body weight per day for healthy older adults and approximately 1.2–1.5 grams per kilogram during acute or chronic illness, malnutrition risk or recovery.
For adults who train with resistance (weights, bands, machines), intentionally lose weight, recover from inactivity or face other catabolic pressures, approximately 1.2–1.6 grams per kilogram per day is often a useful working range, if medically appropriate. Across resistance-training studies, benefits from progressively increasing protein appear to level off near 1.6 grams per kilogram per day for healthy adults, although individual requirements vary.
- Protein at each meal: Total daily protein matters, but the body cannot store a large reserve of amino acids specifically for use at the next meal. Distributing protein across three or four means repeated opportunities to stimulate muscle protein synthesis. That is much more effective than expecting one large dinner to compensate for a low-protein breakfast and lunch.
A practical per-meal target is approximately 0.3–0.4 grams of high-quality protein per kilogram, or about 25–40 grams per meal. Larger adults, older adults with substantial anabolic resistance and people recovering from illness will need the upper end of that range.
Each meal should provide all nine essential amino acids, meaning the amino acids the body cannot manufacture in adequate amounts. Leucine acts as an important signal, but the remaining essential amino acids supply the raw materials needed to complete the proteins that leucine tells the cell to build.
- The leucine threshold: Younger muscle usually responds to approximately 2 grams of leucine, but older muscle requires a leucine intake of about 3 grams to produce a robust muscle protein synthesis response. You can use 2.5–3 grams of leucine per meal as a practical guideline, but it isn’t an exact requirement for everyone.
Example: A meal containing 30–40 grams of whey, dairy, eggs combined with dairy, poultry, fish, lean meat, or an appropriately formulated plant-protein blend will often reach that range naturally. Adding isolated leucine is unlikely to provide proportional additional benefit when the meal already contains enough complete protein.
Exercise multiplies and intensifies muscle building signals
Essential amino acids and resistance exercise each independently stimulate muscle protein synthesis, but it is their combined effect that provides a much greater response, especially in older people. Mechanical tension (resistance) tells muscle tissue where adaptation (more muscle) is needed. Protein provides the biochemical signal and amino-acid substrate needed to carry out the recovery and growth.
KEY POINT TO KEEP IN MIND: Nutrition alone cannot replace resistance training. Hormone therapy alone cannot replace adequate protein nutrition OR resistance training. ALL THREE ARE NEEDED.
Think of it this way:
- Protein supplies the building block materials.
- Resistance training provides the construction plan.
- Optimal hormone balance helps the construction crew respond.
So, let’s dig into the roles played by the various key hormones players in muscle maintenance, growth and your long-term strength and resilience .
The Hormonal Environment
Hormones do not act as simple on-and-off switches. Some directly promote protein synthesis, some mainly restrain breakdown, and others influence blood flow, glucose availability, mitochondrial function, oxidative stress, inflammation, appetite, recovery or the ability to train.
Testosterone in men
Testosterone provides the clearest direct sex-steroid stimulus for muscle anabolism. It binds androgen receptors in skeletal muscle, alters gene transcription, supports satellite cells involved in repair and hypertrophy, increases reuse of intracellular amino acids and promotes enlargement of muscle fibers. A man with untreated hypogonadism may still respond minimally to increased protein intake and resistance training. But excellent nutrition cannot correct deficient androgen-receptor signaling, just as testosterone cannot supply missing essential amino acids or replace mechanical loading. They work together; one along cannot replace the benefits of both.
Hypogonadism (Low T): What Does Testosterone Therapy add?
Hypogonadism refers to sustained and confirmed serum total testosterone levels below 300 ng/dl, initially measured with an accurate fasting morning test and confirmed on a separate morning, according to The Endocrine Society guidelines. “Low T” should not be diagnosed just from symptoms such as fatigue, low libido, loss of muscle strength, or one borderline laboratory result.
A complete evaluation of “Low T” should include additional lab tests for causes of low T (such as high prolactin, spike protein damage, diabetes, metabolic syndrome) and evaluation of contributing factors such as other medical conditions (diabetes, obesity, sleep apnea, marijuana use, etc), medications (statins, antihypertensives, SSRI/SNRI/antipsychotics, anticonvulsants, opiates, and others), alcohol abuse, vaccine damage, chronic illness. All of these factors can affect testosterone production and function, and I discussed them in detail in our Faith Over Fear Seminar on Testosterone for Men: From FAT to FIT
Physiologic testosterone replacement therapy, or TRT, aims to restore deficient testosterone to appropriate levels of a healthy man—not to create the supraphysiologic concentrations used in body builders that also carry significant adverse health effects. In hypogonadal men, TRT increases lean mass and reduces fat mass to a greater degree than it improves strength, power or mobility unless TRT is combined with optimal protein intake and resistance training. The combination of all three produces optimal benefit.
TRT also requires discussion of fertility if being used for confirmed hypo-gonadism in men who desire to have children, since exogenous testosterone can suppress sperm production.
During testosterone therapy, physicians should be monitoring symptoms and clinical response and check lab tests every few months for testosterone concentrations, hematocrit and hemoglobin status, metabolic markers, and prostate-related risk.
Hormones in women
Women produce testosterone as well as estrogen, and skeletal muscle contains both androgen and estrogen receptors. However, the evidence for hormone therapy as a muscle building intervention differs considerably between women and men.
Estradiol after menopause
Estradiol supports muscle repair, mitochondrial function, metabolic flexibility, connective-tissue formation, and acts as an antioxidant at the muscle cell membrane to help protect against oxidative damage during daily activity and exercise. It plays a significant role in muscle tissue’s beneficial response to exercise, and when estradiol declines, muscle pain with exercise typically increases (often loss of estradiol is misdiagnosed as fibromyalgia!). Exercise combined with estrogen replacement therapy shows promise as a way to help maintain lean mass after menopause. In one small study of early postmenopausal women, 12 weeks of progressive resistance training increased muscle cross-sectional area by 7.9% with transdermal estradiol included as therapy when compared with 3.9% increase with exercise in the placebo group. That result strongly suggests estradiol can enhance training responsiveness in early-postmenopausal women. Estradiol therapy after menopause has a major impact to improve sleep (and nocturnal growth hormone secretion that helps repair muscle overnight), reduce vasomotor symptoms, reduces muscle pain and stiffness after exercise, improves strength and function of tendons and ligaments, protects bone. For all these reasons, estradiol therapy plays a major role in making regular training more tolerable and therefore likely!
Progesterone and the uterus
A woman who still has her uterus and decides to take systemic estradiol therapy must also have progestogen in adequate dose and duration to to protect the endometrium from estrogen-driven hyperplasia and possible later risk of uterine cancer. That is the primary reason to include micronized progesterone or a testosterone-derived progestin such as norethindrone in a menopausal hormone regimen, not specifically for benefits on muscle protein synthesis.
Testosterone in women
Research has confirmed that female skeletal muscle responds to androgen signaling and that that testosterone can stimulate muscle protein synthesis in postmenopausal women, but the most significant benefits occur in women after estradiol is restored to premenopausal optimal levels. Larger clinical evidence, however, has not demonstrated a statistically significant improvement in lean mass or muscle strength from testosterone therapy alone in post menopausal women. Current evidence does not support prescribing testosterone to women routinely to prevent age-related muscle loss, improve energy or act as a general anti-aging therapy.
If testosterone is prescribed for an appropriate indication, treatment should maintain concentrations within the physiologic premenopausal female range and testosterone should be started AFTER estradiol levels restored to optimal ranges so as to avoid adverse androgenic excess side effects. Male products, even diluted, are far too concentrated to be safely used in women. Doses need to be tailored to the lower levels for female therapy, and in the United States, have to be obtained from reputable compounding pharmacies since there is still NO FDA-approved product for women.
I will talk more in a future Health Tip about the differences, risks, and benefits of FDA-approved bioidentical hormones (available in the USA since 1975 in various forms for estradiol and progesterone) versus compounded hormones from a local compounding pharmacy. I have been teaching seminars and CME classes for physicians and nurses on this subject since 1985, but it is beyond the scope of today’s Health Tip.
Cortisol: Mixed Effects
Cortisol as a hormone is both beneficial, critical to life, and can also cause serious adverse effects when present in excess over prolonged periods. It is not inherently harmful. A morning rise helps the body awaken, and temporary increases during exercise, infection or acute stress mobilize energy needed to meet a challenge.
The problem arises with excess cortisol—whether due to Cushing syndrome, chronic systemic glucocorticoid treatment, severe illness or a prolonged combination of stress, inactivity and inadequate nutrition.
Cortisol excess in Cushing’s disease –or prolonged use of corticosteroid medications—leads to muscle breakdown and suppression of muscle protein synthesis, increase protein degradation, interfere with insulin and IGF-1 signaling and preferentially weaken proximal muscles around the hips and shoulders.
In a controlled 28-day bed-rest experiment, investigators raised cortisol to concentrations observed during serious illness. Participants lost 1.4 kilograms of lean leg mass, experienced a 28% reduction in leg-extension strength and showed a substantial reduction in muscle protein synthesis. The combined effect was much larger than bed rest alone!
The goal should not be to suppress every cortisol rise with a supplement. The more useful strategy is to identify chronic excess cortiso exposure, treat the underlying illness, avoid unnecessary prolonged steroid therapy, provide sufficient energy and protein, and maintain or restore muscle loading as safely and quickly as possible.
Psychological stress usually threatens muscle indirectly through sleep disruption, missed meals, alcohol use, reduced activity, overly aggressive dieting or poor training recovery. Prolonged stressful situations or long-term overtraining without adequate rest or easy days is where the problems begin. For example, a hard workout can “tear” muscle fibers and breakdown muscle but during a proper recovery the muscles heal and rebuild and get stronger.
Insulin and diabetes
Insulin does more than lower blood glucose. In skeletal muscle, it increases glucose uptake, supports glycogen restoration, recruits microvasculature and helps deliver amino acids while suppressing muscle-protein breakdown.
Older muscle becomes resistant to these protein-anabolic effects, even in the absence of diabetes. In one experiment, increasing muscle perfusion during insulin exposure allowed older adults to increase muscle protein synthesis and shift from negative to positive net muscle-protein balance, showing that nutrient delivery can be as important as nutrient availability.
Type 2 diabetes adds hyperglycemia, vascular dysfunction, mitochondrial impairment, inflammation and intramuscular fat to the problem. Impaired insulin and IGF-1 signaling can reduce protein-synthesis pathways while increasing autophagy and ubiquitin–proteasome activity, two systems involved in dismantling cellular proteins.
The relationship then becomes bidirectional:
- Less active muscle reduces the body’s capacity for glucose disposal.
- Insulin resistance weakens blood flow, nutrient delivery and anabolic signaling.
- Diabetes complications reduce activity and exercise tolerance.
- Further muscle loss worsens metabolic reserve.
Loss of muscle (sarcopenia) and frailty in older adults with type 2 diabetes are associated with poorer functional outcomes and higher mortality risk, making strength preservation an important part of metabolic care.
This is why I recommend resistance training in addition to aerobic activity, post-meal walking, and treatment of sleep apnea as important components of appropriate insulin resistance and diabetes management. This combination can be an effective strategy to improve insulin sensitivity while preserving muscle.
Growth hormone and IGF-1
Growth hormone stimulates production of insulin-like growth factor 1, or IGF-1, and together they influence tissue repair, satellite cells, protein turnover and body composition. Activity within this axis generally declines with age, but a normal age-related decline does not establish adult growth-hormone deficiency.
Recombinant growth hormone Rx medicine is appropriate for selected adults with confirmed pituitary-related GH deficiency. It is not an evidence-based anti-aging or routine therapy for muscle loss, and is not a therapy approved to reverse normal endocrine aging.
In healthy older adults, GH may increase measured lean mass without reliably increasing contractile strength. Trials also report edema, joint pain, carpal-tunnel symptoms, gynecomastia, impaired fasting glucose and diabetes, so the benefit–risk balance does not support routine use for muscle preservation.
Resistance exercise, adequate sleep, sufficient energy and protein, and optimal physiologic estradiol/testosterone therapy, plus treatment of underlying illness offer safer ways to support normal GH–IGF-1 physiology.
Thyroid and muscle
Thyroid hormone regulates mitochondrial activity, metabolic rate, muscle-fiber characteristics and contraction–relaxation kinetics. Excess thyroid and low thyroid hormone levels adversely affect the health of muscle tissue and can cause loss of muscle mass and strength.
Hypothyroid myopathy causes fatigue, cramps, reduced muscle protein synthesis, stiffness, exercise intolerance, myalgia and slowly progressive proximal weakness. Muscle enzymes such as creatine kinase may rise, although the laboratory abnormality isn’t reliable for diagnosis since abnormal CK levels do not always parallel symptom severity.
Hyperthyroidism increases metabolic demand and protein turnover, potentially allowing muscle breakdown to outpace synthesis. It commonly causes wasting, tremor, exercise intolerance and weakness affecting the thighs, hips and shoulder girdle. It may also cause significant damage to cardiac muscle and trigger angina with or without arrhythmias.
Restoring a euthyroid state—normal thyroid function—can improve muscle size and strength if thyroid disease caused the impairment. Both overt and subclinical hyperthyroidism have been associated with lower thigh-muscle area and strength that improved after proper treatment in clinical research.
Vitamin D and PTH
Vitamin D functions as a prohormone and participates in calcium regulation, neuromuscular signaling and bone–muscle interaction. Severe deficiency can produce proximal weakness, including difficulty rising from a chair or climbing stairs, while bone loss and fractures can trigger inactivity that further accelerates anabolic resistance.
Low vitamin D can increase parathyroid hormone, or PTH, as the body attempts to maintain blood calcium. Persistent secondary hyperparathyroidism increases bone turnover and may compound pain, fracture risk and loss of physical function.
Correcting a documented deficiency makes sense, but high-dose vitamin D does not reliably increase strength or physical performance when vitamin D status is already sufficient. The goal is optimal, adequate vitamin D level as I explained in detail in my earlier Health Tip.
Other hormonal influences
Myostatin is a muscle-derived signaling protein that limits muscle growth through activin receptors and SMAD signaling. Although myostatin-blocking therapies can increase lean mass in some experimental settings, they have not consistently produced corresponding improvements in strength or function and are not standard treatments for age-related muscle loss.
DHEA and DHEA-S decline with age and serve as precursors for androgen and estrogen synthesis. DHEA supplementation has not consistently improved body composition, strength, aerobic capacity or insulin sensitivity in older men. In older women DHEA alone can cause adverse androgen excess effects since without functioning ovaries, women cannot convert DHEA to either end product of estradiol or testosterone. DHEA is not recommended for menopausal women in lieu of physiologic estradiol alone or with progestin in women with a uterus, and addition of testosterone when appropriate for women.
Appetite-regulating signals—including leptin, ghrelin and GLP-1—these affect muscle primarily through food intake, body weight and insulin sensitivity. Any disease, medication or weight-loss strategy that produces marked appetite suppression or rapid weight loss can create insufficient energy and protein intake unless the plan actively protects muscle. This is a critical issue leading to muscle loss in people taking GLP-1 medications.
Dr. Vliet’s Recommends: A Practical Action Plan
Overcoming anabolic resistance requires several coordinated signals and an organized, systematic plan. From all my years working in the specialized focus of integrative endocrine evaluations tied into preventive medicine, wellness and resilience strategies, I think it is critical to have a baseline comprehensive evaluation of all of your endocrine systems, using the gold standard blood (serum) tests. This gives you a reliable starting point. Then, the most effective plan is an integrated one that combines medical treatment with the eating plan and supplements we discussed last week: the right amount, type and timing of protein, quality targeted supplements tailored to your lab test results and individual needs, mechanical loading (resistance training), daily movement, recovery and quality sleep.
THE BOTTOM LINE: SUMMARY OF YOUR ACTION STEPS:
Assess reversible causes: don’t just chalk it up to “getting older!” Talk with your healthcare professional about a thorough laboratory and clinical evaluation of unexplained weakness, unrelenting fatigue, frequent injuries, rapid functional decline, unintentional weight loss or poor exercise recovery, repeated falls, unexplained muscle wasting, inability to rise from a chair, easy bruising with wide purple stretch marks, chronic systemic steroid exposure, severe fatigue with weight change, or a sudden decline in exercise capacity. These features may indicate an endocrine, inflammatory, neurologic or systemic illness—not “normal aging.”
Treat true deficiencies identified on reliable, reputable lab testing. I have addressed comprehensive evaluations such as we list in our resources on our website in earlier Health Tips, so I will not repeat them here.
Build every meal: Aim for three or four meaningful protein meals rather than concentrating most protein at dinner. Use approximately 0.3–0.4 grams per kilogram per meal, often 25–40 grams. Include a complete essential-amino-acid profile. Use approximately 2.5–3 grams of leucine per meal as a practical older-adult guideline. Target roughly 1.2–1.6 grams of protein per kilogram per day when active, training, losing weight or facing elevated muscle-loss risk, individualized for health status. Protect total calorie intake; protein cannot fully compensate for severe under-fueling which can happen when eliminating entire food groups (i.e. complex carbohydrates). People with moderate-to-severe kidney disease, advanced liver disease, complex illness or substantial malnutrition should obtain individualized protein guidance.
Train with progression. Perform resistance exercise at least two or three times weekly as health and recovery allow. Train the major movement patterns—squatting or chair rising, hinging, pushing, pulling, carrying, calf work and trunk stabilization—while gradually increasing resistance, repetitions, range of motion, control or total work.
Move between workouts. Formal lifting does not cancel an otherwise sedentary week. Walk regularly, interrupt prolonged sitting and consider 10–15 minutes of easy walking or cycling after meals to support glucose control, circulation and nutrient delivery. Regular moderate activity before protein intake can improve nutrient-stimulated muscle perfusion and muscle protein synthesis in older adults. Think of your daily cardiovascular type of movement as part of the anabolic program, not merely as calorie expenditure.
Use supplements selectively. Supplements should close a nutritional gap or enhance a well-designed training program—not compensate for inadequate food, sleep or medical care.
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