The Gut-Muscle-Immune Axis: How Mitophagy Rewires Your Body for Longevity

The Dr. Gabrielle Lyon Show | January 6, 2026
Guest: Dr. Anurag Singh
Primary Theme:
This episode explores the interplay between the gut, muscle, immune system, and mitochondrial function—collectively termed the "gut-muscle-immune axis"—and how targeted strategies like mitophagy induction may transform longevity, healthspan, and resilience to age-related decline.

Key Episode Segments & Insights

1. Defining Immune System Health and Aging

Timestamps: 00:00 – 10:40

• Misconceptions in Standard Practice:
  Most physicians assess immune health via a single marker, C-reactive protein (CRP), which only reflects inflammation and not functional immunity.
• Immune Cell Decline With Age:
  • Total leukocyte and lymphocyte counts diminish as we age, undermining the body’s defense (05:00)
  • The thymus, crucial for immune cell development in youth, undergoes involution by age 20, seeding the body with immune "ammo" that wanes by age 50–60 (06:05–06:35)
• Hallmarks of Immune Aging:
  • Damage to both mitochondria and immune cells linked to diseases like inclusion body myositis (03:19)
  • Immune cell "exhaustion" and chronic low-grade inflammation (“inflammaging”) are central to immune decline

Quote:
"A lot of doctors...think about the immune system with one marker, C reactive protein. That's all they do...Now, what happens with aging is...your total leukocyte counts go down and your total lymphocyte counts go down." – Dr. Singh (00:04)

2. The Muscle–Immune System Relationship

Timestamps: 10:41 – 15:56

• Muscle as an Immune Organ:
  A significant number of immune cells reside in skeletal muscle, serving as sentinels for the body (12:28)
• Muscle Aging Mirrors Neural Aging:
  Phenomena like sarcopenia (muscle mass and function loss) overlap with “inclusion body myositis,” similar to protein deposits in Alzheimer’s but in muscle (01:34–03:19)
• Exercise as a Pillar of Longevity:
  Maintaining muscle through movement and nutrition is one of the three pillars of healthy aging. The others: the brain and immune system (15:18)

Quote:
"The relationship is, there are a lot of immune cells in the skeletal muscle...the top pathways that light up are linked to two biological hallmarks of aging: poor mitochondria and immune cell dysregulation." – Dr. Singh (12:57)

3. Mitophagy, Autophagy, and Interventions for Aging

Timestamps: 15:57 – 34:05

• Definitions:
  • Autophagy: Cellular "self-renewal," clearing damaged organelles (16:19)
  • Mitophagy: Targeted autophagy of mitochondria, essential for cellular energy and health (16:19)
• Urolithin A and Recent Breakthroughs:
  • Dr. Singh references a recent Nature Aging clinical trial: Urolithin A, a gut-derived postbiotic, stimulates mitophagy, increases mitochondrial mass/function in immune cells, and raises counts of youthful ("naive") immune cells (19:19–21:22)
  • After just 28 days, subjects had a 20% increase in immune cell mitochondrial mass and a shift from glucose to fatty acid metabolism (24:16)
• Postbiotics and Gut Health:
  Only ~30–40% of adults naturally produce urolithin A; this depends on gut microbiome composition and diet (27:03–27:33)

Quote:
"What we found is...these naive CD8 T cells, these stem-cell-like youthful immune cells, could we proliferate them...and would having better mitochondria lead them to dividing and having more? What we find is...both are true in this cohort of aged 50-year-old plus individuals." – Dr. Singh (19:19)

4. Pathways, Mechanisms, and Targeted Compounds

Timestamps: 34:06 – 59:14

• Biological Pathways:
  • Key proteins in mitophagy: PGC1-alpha, parkin (29:08–29:34)
  • Autophagy inducers: exercise, caloric restriction, compounds like urolithin A and spermidine (43:35)
• Synergy Between Exercise/Supplements:
  • Exercise and urolithin A supplementation have additive effects on muscle and immune health (50:41–51:26)
  • Blood-based immune cell mitochondrial markers may soon become mainstream (62:04)

Quote:
"Autophagy is the broad umbrella, and mitophagy is singularly focused on the mitochondria...if you're looking to boost your mitochondrial health in a very targeted way, that's where urolutein A comes in." – Dr. Singh (44:10)

5. Practical Recommendations & Clinical Markers

Timestamps: 59:15 – 66:47

• Testing Immune Health:
  • Total leukocyte and lymphocyte counts in blood are meaningful markers (63:12–63:20)
  • Optimal lymphocyte percentage should stay at 20–30% of leukocytes; drops with age are concerning (63:20)
  • Even a 1–2% increase in lymphocyte count is "clinically meaningful" (63:19)
• Muscle Activation for Immunity:
  • Minimal effective dose: 30 minutes of movement, three times a week; intensity can be moderate (30:11)
  • Movement, not necessarily resistance training, is what matters most for immune activation (59:14–59:49)

Quote:
"I think you have about 20–30% of all your total leukocytes would be lymphocytes. And they decline, probably like muscle declines...I think even a 1–2% increase...is clinically meaningful. Like crazy." – Dr. Singh (63:20)

6. Expanding the Science: Brain Health, Inflammation, and Future Trials

Timestamps: 66:48 – 83:35

• Brain Health Frontier:
  • Evidence that urolithin A can cross the blood-brain barrier—potential for neuroprotection (41:18–41:34)
  • Selenium and ergothioneine as potential brain protectants (81:10–81:59)
• Joint and Cartilage Health:
  Urolithin A upregulates autophagy and reduces inflammation in osteoarthritic cartilage (39:15)
• Ongoing and Future Trials:
  • Long-term (>6 months) studies underway to assess healthspan outcomes in the elderly
  • Combined therapy with urolithin A and standard cancer immunotherapy being investigated

Quote:
"I call it my gut trifecta: gut, muscle, immune axis. And now also...the brain. If you lose the capacity of the healthy microbiome and these postbiotics, you're affecting your muscle, your brain, and your immune system." – Dr. Singh (27:46)

Notable Quotes & Memorable Moments

• "You cannot deceive the immune system. You've lost your naive CD8 T cells. No placebo in the world...will have that meaningful change. Muscle, it will. Immune system, you cannot." – Dr. Singh (61:01)
• "If you can get autophagy and mitophagy revved up as the foundation of your cellular health, anything that you're layering...they will work better just because now you have the real estate to do whatever you want to do." – Dr. Singh (45:19–45:51)
• "The only candidate right now we have is Metformin. To be honest." – Dr. Singh on repurposed longevity drugs (70:06)

Actionable Takeaways

• Assessing Immune Health:
  Regularly monitor total leukocyte and lymphocyte counts; prioritize a range akin to your younger years (63:12–63:20).
• Lifestyle for Longevity:
  Consistent exercise (3x30 minutes/week), a diet supporting healthy microbiota, and minimizing inactivity are paramount for muscle and immune vitality (30:11, 59:14).
• Mitophagy Support:
  Evidence supports urolithin A supplementation (1,000 mg daily) to enhance mitochondrial function, especially in those not producing it naturally (21:37, 27:09). Exercise and nutrition are foundational.
• Supplement Synergy:
  Creatine, vitamin D, and certain polyphenols can complement mitophagy-inducing strategies; vitamins C and zinc less supported for immune boosting (47:35–48:21).
• Future Frontiers:
  Watch for blood-based immune cell mitochondrial diagnostics and multi-compound (mitophagy + brain health) supplements in clinical trials (66:47, 82:21).

Quick Segment Overview

• [00:00 – 10:40] – Immune system basics, aging, and cellular decline markers
• [10:41 – 15:56] – Muscle as an immune organ, dual decline, connection to longevity
• [15:57 – 34:05] – Definitions: autophagy vs. mitophagy, urolithin A’s role, recent trials
• [34:06 – 59:14] – Mechanisms, compound synergies, practical lifestyle approaches
• [59:15 – 66:47] – Real-world clinical markers, advice for practitioners and individuals
• [66:48 – end] – New science in brain/joint health, future studies, and closing thoughts

Tone:

Conversational, evidence-focused, transparent, and generally optimistic about the synergy between lifestyle and emerging science in promoting healthy aging.

For further exploration and up-to-date research, check Dr. Lyon’s show notes and referenced studies.