I got a few vials of MOTS-c and SS-31, and if I understand correctly, this seems like an interesting complementary combination for improving mitochondrial function. MOTS-c activates AMPK, while SS-31 targets cardiolipin and works as an antioxidant. Here’s what I was thinking: MOTS-c: subcutaneous, 5 mg, 2x per week, for 4 weeks SS-31: subcutaneous, 2 mg daily, 3x per week, mainly on rest days Does this protocol make sense, and what kind of supplements could I add alongside to maximize the benefits of the cycle?

This whole “six-stage agonist” idea reads like a playground contest where six-year-olds are trying to one-up each other without thinking through the consequences. One kid says, “I can eat the most candy,” the next says, “Well I can stay up all night,” another brags, “I can ride my bike with no hands,” and pretty soon the game spirals into chaos everybody competing, nobody coordinating, and the end result is a bunch of sick, cranky kids. That’s exactly what happens when you try to bolt GLP-1, GIP, glucagon, IGF-1, Klotho, and myostatin inhibition together into a single product. Each of these signals has real, powerful effects on metabolism, growth, and cellular resilience, but they pull in opposite directions, act on different timelines, and demand very different dosing windows. Instead of synergy, you create noisy cross-talk that leaves the body trying to follow six conflicting orders at once. True optimization doesn’t come from piling on more levers or chasing the newest shiny receptor target it comes from respecting the intelligence of the cell, reducing signal noise, and using surgically precise interventions at the right time and in the right tissue. A “GLP-1 + GIP + glucagon + IGF-1 + Klotho + anti-myostatin” cocktail is mechanistically incoherent because it stacks pathways that biochemically push in opposite directions, on different clocks, in different tissues. GLP-1R and GIPR are Gs-coupled incretin receptors that raise cAMP/PKA and potentiate β-cell insulin secretion, slow gastric emptying (GLP-1), and alter CNS appetite; GCGR is also Gs-coupled but in hepatocytes it spikes cAMP/PKA to drive glycogenolysis and gluconeogenesis, directly opposing the glucose-lowering aim of the incretins and serine-phosphorylating IRS1 to blunt insulin signaling in liver. IGF-1R is an RTK that activates IRS→PI3K→AKT→mTORC1 and MAPK/ERK to promote hypertrophy and nutrient storage, while soluble Klotho evolved as a longevity brake: it partners with FGF23 for phosphate/Vit-D control and independently dampens IGF-1/insulin signaling and shifts cells toward FoxO-mediated stress resistance and autophagy i.e., the biochemical opposite of sustained mTORC1 drive. Myostatin inhibition removes SMAD2/3 repression at ActRIIB, disinhibiting satellite cells and mTORC1 in muscle; pair that with IGF-1 and you push strong anabolism in myofibers, but the liver is simultaneously being told by glucagon to export glucose and lipids while adipose receives a GIP signal that favors storage so partitioning gets noisy. Add hard constraints from pharmacology: receptor stoichiometry and PK don’t line up. IGF-1 (IGFBP-bound) has long half-life and broad tissue exposure; GLP-1/GIP need DPP-4 protection and act over minutes to hours; glucagon clears fast but hits liver immediately; Klotho’s effects are slow, endocrine, and context-dependent; anti-myostatin requires sustained exposure for weeks to remodel transcription. One fixed dose can’t simultaneously achieve the right receptor occupancy across these targets: the concentration that meaningfully engages IGF-1R will overshoot GLP-1R CNS effects; the dose that meaningfully inhibits myostatin in skeletal muscle will not “time-match” the brief hepatic cAMP bursts from glucagon; and any hepatic PKA surge will antagonize the insulin/IGF-1 signaling you need for clean glycogen and protein synthesis. Think of it like six foremen shouting conflicting orders on a construction site: IGF-1 and anti-myostatin demand “build muscle now,” Klotho says “slow growth and repair the scaffolding first,” GLP-1/GIP say “bring in insulin and store nutrients,” glucagon yells “ship the materials back out of the warehouse,” and the clock for each foreman runs at a different speed. The “peer-reviewed” reality is that the only reason GLP-1/GIP/GCGR tri-agonists can work in trials is because they are engineered single peptides with tuned receptor bias and potency ratios to achieve a net, phase-appropriate phenotype; bolting on IGF-1, Klotho, and anti-myostatin as separate levers breaks that balance and guarantees asynchronous, tissue-mismatched signaling. The likely story arc is predictable: week 1 you feel appetite suppression and see scale weight drop from GLP-1 physiology while hepatic glucagon spikes make glucose swing; by week 2–4 IGF-1 and anti-myostatin start pushing muscle protein synthesis but collide with hepatic PKA-mediated insulin resistance and GIP-biased adipose storage, so nutrient partitioning becomes erratic; by weeks 4–8 Klotho’s brake on IGF/insulin signaling and phosphate/Vit-D shifts muddy recovery and mitochondrial quality control, leaving you with jittery glycemia, inconsistent pumps, GI side effects, possible edema or mineral issues, and a plateau where fat isn’t reliably falling and muscle isn’t cleanly accruing. Instead of a symphony you get six instruments in different keys, different tempos, and different rooms the score reads “recomp,” but the sound is chaos.

Stories are only as powerful as the actions they inspire. In the first part of this series, we followed the earliest domino of kidney disease back to the mitochondria, where stress piled up until adaptation became maladaptation. In the second part, we mapped out the signaling pathways the master switches of energy, growth, inflammation, and repair that tilt health toward decline when balance is lost. In the third part, we looked at the biomarkers, the fingerprints left behind by falling dominoes, and saw how they let us measure stress long before kidneys reach crisis. In the fourth part, we climbed the intervention pyramid, starting with the free but foundational acts of sleep and stress repair, moving through exercise and nutrition, and ending with advanced tools like peptides and devices. Now it’s time to bring everything together into a practical framework. Cellular medicine is not about chasing symptoms; it’s about restoring the cell’s ability to adapt. That means sequencing interventions in a way that stabilizes the base before layering in complexity. It means aligning choices with molecular mechanisms, so that every hour of sleep, every meal, every training session, and every carefully chosen compound feeds into the same theme: nudging mitochondria back into resilience, quieting maladaptive signals, and protecting the delicate sieves that filter our blood. Let’s imagine the cell not as a machine but as a city. The mitochondria are its power plants, the endothelial cells its bridges, the immune signals its alarm systems, and the sirtuins its seasoned repair crews. In kidney disease, the power plants are overloaded, the bridges are cracking, the alarms are stuck blaring, and the repair crews are underpaid and understaffed. Our goal is not to replace the city it’s to re-train it, re-fuel it, and restore harmony between its systems. The protocol that follows is built on four layers, like the pyramid described earlier. Each layer feeds into the next. Lifestyle calibrates the environment. Exercise builds capacity. Nutrition signals adaptation. Advanced tools accelerate resilience. None of these can work alone; together, they create synergy. And synergy is what the kidney, an organ of fine balance, requires. Here’s how it comes together in practice:

One of the best parts of this journey is having mentors who push me to keep learning and questioning. @Elizabeth Yurth has been that kind of mentor for me. She’s not only a brilliant mind in cellular medicine, she’s also someone who constantly reminds me to dig deeper, challenge assumptions, and ask better questions. It was actually Dr. Yurth who got me to revisit the research around Fatty15. Her guidance along with the incredible work she’s doing through the Boulder Longevity Institute and her Human Optimization Academy has been a game-changer for me and so many others. Having people like her in my corner makes me a better student, a better teacher, and hopefully of better service to all of you. With that in mind, I wanted to share some thoughts on Fatty15, the hype, the skepticism, and what we can really learn from it when we zoom out and ask deeper questions. Fatty 15 has become one of the most talked-about molecules in the wellness and longevity space, not because it is new to science, but because of the way it has been packaged and sold. Marketed as the first “essential” odd-chain saturated fatty acid, Fatty 15 (the supplement form of C15:0) promises to stabilize membranes, reduce inflammation, and extend healthspan. For many, the narrative is seductive: here is a nutrient that has been hiding in plain sight, maligned by decades of anti-saturated-fat dogma, finally rebranded as a cornerstone of cellular resilience. But step back from the marketing and look at the science, and the picture becomes more complex. Lipidologists and metabolic researchers, including Dr. Dayan Goodenowe, argue that high levels of pentadecanoic acid in the blood are not causal but correlative. In other words, elevated C15:0 is a marker of robust lipid metabolism, not the reason for it. To use an analogy, it’s like noticing that healthy cities all have clean street signs and then deciding that shipping in more street signs will fix a crumbling city. The signs are a marker of order; they are not the thing that creates it. Supplementing with C15:0 without repairing upstream dysfunction may not move the needle and in some cases, may even make things worse.

One of the most powerful ideas in cellular medicine is that the “invisible” can be made visible. The pathways and dominoes that tumble inside our cells aren’t just abstract concepts—they leave fingerprints that can be measured. Biomarkers are those fingerprints. They are the translation between mechanistic stress and clinical awareness, the way we can peer inside the dance of mitochondria, immune tone, vascular health, and repair. In kidney disease, the biomarker story tells us exactly how the first domino set the others into motion. Think first of redox balance. When mitochondria lean too heavily on glycolysis and electron flow becomes inefficient, NAD+ pools drain and NADH builds. The NAD+/NADH ratio is the gold-standard reflection of redox status, showing whether the cell is running smoothly on oxidative phosphorylation or choking on excess reducing equivalents. A low ratio means sirtuins like SIRT1 and SIRT3 are silenced, leaving DNA less protected and repair less efficient. It’s like a city that once had a thriving team of repair crews, now sitting idle because their wages dried up. Alongside this, the lactate-to-pyruvate ratio offers a more accessible proxy. High lactate with relatively low pyruvate tells us glycolysis has become dominant, confirming that cells are leaning on the quick-and-dirty survival pathway rather than efficient respiration. As the imbalance spreads outward, we can track inflammation. hsCRP is a workhorse biomarker here. Elevated levels tell us that NF-κB has been turned on, driving a persistent inflammatory tone. But hsCRP alone is blunt—it’s like knowing a fire alarm is ringing but not knowing which room the fire is in. Cytokine panels offer more nuance: IL-6 and TNF-alpha elevations confirm pro-inflammatory dominance, while low IL-10 shows that resolution is missing. In kidney disease, this trio tells us not just that inflammation is present, but that it is locked into the maladaptive side of the cycle. The vasculature offers its own set of clues. Nitric oxide metabolites can be measured directly, reflecting endothelial flexibility. Low NO levels indicate that PI3K/AKT and eNOS are faltering. Flow-mediated dilation (FMD), a functional vascular test, demonstrates whether blood vessels can widen smoothly in response to increased flow. Poor FMD is a functional echo of what is happening in the kidney’s glomeruli: rigid vessels transmitting mechanical stress downstream. Add in ICAM and VCAM, adhesion molecules that rise when endothelial walls are inflamed, and you have a detailed map of how the traffic lights of circulation are failing.