https://x.com/photobiogenesis/status/1811149241202405625Bryce Hanna
@photobiogenesis
"Calcification" is a misnomer, it should be called "phosphication" or another term that highlights the process's primary dependence of phosphate rather than calcium
Calcium crystals in bone, teeth, and soft tissue are all calcium PHOSPHATE crystals
Allow me to explain, It's difficult or impossible to become "deficient" in circulating calcium because of the large reservoir that exists in bone. When calcium intake is low, hormones like parathyroid hormone (PTH) are elevated which increase breakdown of bone to release calcium.
PTH also elevates phosphate in the bloodstream, this occurs because calcium and phosphate are both released from bone, so while PTH promotes phosphate excretion it's still linked to phosphate accumulation when dietary Calcium:Phosphate ratio is off
Klotho is an important factor in aging, increasing it significantly improves longevity in rodents.
While it's often conceptualized as a big-picture protein with many actions, at its heart is the simple action of decoupling calcium and phosphate metabolism. Klotho simultaneously activates channels that recycle calcium while blocking phosphate recycling, It's also a coactivator for the fibroblast growth factor (FGF) receptor family, which have various protective effects and include factors like FGF21 and FGF23
Klotho is stimulated by various factors:
- exercise
- sun exposure
- caloric restriction
- omega-3 fats
- eating fructose/sugars
- various polyphenol-rich foods
- medicinal mushrooms
- brown adipose tissue (cold adaptation and thermogenesis)
- melatonin, testosterone, and T3
- nutrients like zinc and vitamin E
There are two subsets of Klotho:
alpha-Klotho regulates calcium phosphate balance primarily, it drives the increase in FGF23 which is responsible for a protective increase in phosphate excretion
beta-Klotho regulates energy intake, food preference, and metabolic rate by coupling with the liver hormone FGF21 which is normally responsible for the anti-aging effects of caloric restriction and methionine restriction
There's a clear axis of pro-fibrosis vs anti-fibrosis factors, and phosphication is the center of this process. Parathyroid hormone, hyperphosphatemia, and catabolic hormones like cortisol and prolactin (stimulated by PTH), all increase pro-fibrotic factors like TGF-beta
Phosphate plays an essential role in metabolism in the form of ATP
Acetyl-phosphate or pyrophosphate may have served as ancient precursors to modern ATP in early life. Excess phosphate is directly toxic to cells and triggers inflammation, oxidative stress, and cancer formation.
Calcium's great benefit to early life may have been its ability to precipitate into insoluble crystals with phosphate. This allows both calcium and phosphate, which act as stress signals in excess, to be stored safely within the organism
Over time this developed into bone
Calcification is dependent on phosphate, and since calcium reserves will always be present we can even argue it's caused by phosphate
Low dietary calcium is what triggers the release of the stress hormone PTH
High dietary phosphate blocks calcium sensing receptors and elevates PTH even in the presence of adequate dietary calcium.
he inverse of this is the anti-phosphication and anti-fibrosis factors
These include FGF23 and Klotho, as well as FGF21, both Klotho and the FGFs need to be present as they act on the same receptor
More dietary calcium is anti-phosphication as it drives phosphate into bone by stimulating calcitonin release and lowers PTH
Modern diets promote fibrosis and calcification through:
- hidden phosphate additives in processed foods
- phosphate pesticide use
- high bean/grain intake which are high in phosphate
- low dairy and leafy green intake which have a favorable Ca:P ratio
- low magnesium and K2 intake, which both reverse existing calcium phosphate deposits
Factors that increase Klotho and FGF21 are highly protective
It's most important to reduce phosphate intake and eat more calcium-rich foods
Caloric restriction, sunlight, exercise, and restriction of animal protein from methionine all raise both Klotho and FGF21
It turns out that high phosphate intake decrease FGF21, but only when paired with a normal or high calorie diet
The increase from caloric restriction or methionine restriction should be enough to offset this
https://t.co/72T3aPuY9L
https://pmc.ncbi.nlm.nih.gov/articles/PMC6213303/
Impaired phosphate excretion from reduced Klotho, excess caloric intake, etc, also drives sodium retention since both sodium and phosphate share a transporter in the kidneys
FGF21 increases insulin sensitivity, and insulin resistance in general drives sodium-sensitive hypertension
There's a large body of evidence that high phosphate intake causes kidney disease, hypertension, calcification and fibrosis, heart disease, diabetes, and more
Eating a better calcium:phosphate ratio (ideally 1:1) is a great way to slow aging and prepare metabolic dysfunction
Human Obesity: Is Insufficient Calcium/Dairy Intake Part of the Problem?
Key teaching points:
Low dietary calcium intake is a significant risk factor for overweight in adults.
Calcium/dairy supplementation may accentuate the impact of a weight-reducing program in obese low calcium consumers.
Calcium/dairy supplementation promotes fecal fat loss and fat oxidation.
Calcium/dairy supplementation favors a decrease in energy intake and a facilitation of appetite control in obese individuals during weight loss.
Phosphate and Klotho
It is concluded that phosphate retention induces complex aging-like phenotypes. Thus, maintaining normal phosphate levels with phosphate binders in patients with CKD with declining Klotho expression is expected to reduce mineral and vascular derangements.
Klotho is a putative aging suppressor gene encoding a single-pass transmembrane co-receptor that makes the fibroblast growth factor (FGF) receptor specific for FGF-23. In addition to multiple endocrine organs, Klotho is expressed in kidney distal convoluted tubules and parathyroid cells, mediating the role of FGF-23 in bone–kidney–parathyroid control of phosphate and calcium. Klotho–/– mice display premature aging and chronic kidney disease-associated mineral and bone disorder (CKD-MBD)-like phenotypes mediated by hyperphosphatemia and remediated by phosphate-lowering interventions (diets low in phosphate or vitamin D; knockouts of 1α-hydroxylase, vitamin D receptor, or NaPi cotransporter).
Phosphate—a poison for humans?
Maintenance of phosphate balance is essential for life, and mammals have developed a sophisticated system to regulate phosphate homeostasis over the course of evolution. However, due to the dependence of phosphate elimination on the kidney, humans with decreased kidney function are likely to be in a positive phosphate balance. Phosphate excess has been well recognized as a critical factor in the pathogenesis of mineral and bone disorders associated with chronic kidney disease, but recent investigations have also uncovered toxic effects of phosphate on the cardiovascular system and the aging process. Compelling evidence also suggests that increased fibroblastic growth factor 23 and parathyroid hormone levels in response to a positive phosphate balance contribute to adverse clinical outcomes. These insights support the current practice of managing serum phosphate in patients with advanced chronic kidney disease, although definitive evidence of these effects is lacking. Given the potential toxicity of excess phosphate, the general population may also be viewed as a target for phosphate management. However, the widespread implementation of dietary phosphate intervention in the general population may not be warranted due to the limited impact of increased phosphate intake on mineral metabolism and clinical outcomes. Nonetheless, the increasing incidence of kidney disease or injury in our aging society emphasizes the potential importance of this issue. Further work is needed to more completely characterize phosphate toxicity and to establish the optimal therapeutic strategy for managing phosphate in patients with chronic kidney disease and in the general population.
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Much of the phosphate in beans and seeds is in the form of inositol phosphates like IP6 which help reduce phosphate intake. Phosphate additives in processed foods are in the form of soluble phosphate salts. Inositol may be protective as well through its ability to form IP6 and bind both phosphate and excess iron in the body. Iron and phosphate clearance may explain some of IP6's anti-cancer effects
Corpora arenacea or "brain sand" is further evidence that it's phosphication not calcification
These are mineral deposits that form in the pineal and various parts of the brain, they're associated with neurodegeneration and aging
They're composed of a combination of calcium phosphate, magnesium phosphate, ammonium phosphate, and some calcite. The overarching common theme is the inclusion of phosphate
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