Notes from book
- Theories
- Aging is driven by damaging processes like Glycation (which causes proteins to cross link and stiffen), Inflammation, and Oxidation (which damages mitochondria and cellās energy production)
- Overgrowth and proliferation of cells (activated by mTOR and IGF-1 ) accelerates aging, while Autophagy (activated by AMPK) allows recycling and clearing out bad molecules and increases lifespan.
- Shortening of Telomere drives aging through Cellular senescence (cells can no longer divide) which releases SASP which causes Inflammation , whereas Sirtuin maintains telomere, repairs DNA, reduces Inflammation, and slows aging
- Methylation impacts biological aging rate through Epigenetics (switching on and off genes). Higher global methylation rate prolongs life
- Aging pathways
- AMPK
- AMP(adenosine monophosphate) activated protein kinase
- Protein kinase is an enzyme that modifies protein by catalyst the transfer of phosphate groups (POāĀ³ā») from ATP to specific molecules
- enzyme is a biological catalyst that accelerates chemical reactions
- AMPK can be activated by exercise, nutrition deprivation/fasting (when AMP/ATP ratio is high)
- Activates ATP generation, inhibits ATP consumption
- Inhibits fat/cholesterol/protein synthesis and cell growth/proliferation, promotes Autophagy /cellular recycling
- Helps decommissioning old mitochondria, which can become actively harmful
- Saturated fat impairs AMPK
- Nicotine boosts AMPK (so smokers sometimes gain weight after quitting). So do barberries (but harmful for infant and during pregnancy and breastfeeding), hibiscus tea and black cumin (by interfering with cell energy production), vinegar (through metabolization of acetic acid), fiber (gut bacteria makes short chain fatty acid from fiber, not including nonfermentable fiber like psyllium)
- Metformin: originally known as glucophage, prescribed for diabetes, can boost AMPK, but the downside is undercutting fitness achievement from exercise, and can be risky at high dose
- Autophagy
- Clears out and upcycles defective proteins, malfunctioning mitochondria, also clears fat out of liver
- Acrylamide (formed carbohydrates are exposed to high temperature, eg potato chips) inhibits autophagy
- Coffee (including decaf) boosts autophagy due to chlorogenic acid (but milk casein protein can bind to it and block absorption)
- Spermidine (initially discovered as tiny crystals formed in semen) boosts autophagy, itās positively charged and can bind negatively charged DNA molecules, stabilizing genetic code for proper translation
- Our cells can make spermidine but declines as we age
- High in wheat germ, tempeh, mushroom (plain white mushroom is better), soybean/soy milk, lentil soup, mango, edamame,
- mTOR
- mechanistic target of rapamycin
- Rapamycin: a bacteria from Easter Island, can create compound that prolongs life by inhibiting mTOR
- mTOR is a protein kinase
- Major regulator of growth, increases cell size and number when activated
- antagonistic pleiotropy: a gene can have a positive effect when weāre young and a negative one when weāre old.
- mTOR suppresses autophagy
- Opposite of AMPK: One goes up as the other goes down, based on nutrient availability
- Restricting a few amino acids suppresses mTOR: methionine, and the three branched-chain amino acids (BCAA): isoleucine, leucine (high in milk), and valine
- acne is considered mTOR driven skin disease
- palmitic acid: a saturated fat found mainly in meat and dairy that has been shown to activate mTOR.
- homocysteine: a methionine breakdown product. Can elevate when vitamin b12 deficient. an mTOR activator
- Telomere
- Each cell has 46 strands of DNA coiled into chromosomes (23 pairs of chromosomes, 1 of the 23 is the sex chromosome, female has 2 X chromosomes and male has 1 X and 1 Y)
- Tip of each chromosome is a protective cap called telomere (each cell has 92)
- Each time the cell divides, a bit of the cap is lost
- When telomere is critically short, emergency signal sends cell to senescence
- Cells restricted from dividing more than about 50 times
- Shortened telomere length associated with arthritis, diabetes, heart disease, kidney/lung/liver failure, osteoporosis, vision loss, less grip strength, less muscle mass, less immunity against cold virus, Alzheimerās disease, and looking older
- Telomere shortening drive aging through Cellular senescence and ensuing SASP inflammation
- Methuselah: Noahās grandfather, longest living figure in Bible (969), advocate of nonviolence and living in peace with animals ā name also given to a bristlecone pine tree in California nearing 4800th birthday ā an enzyme found in its roots called Telomerase can rebuild telomere ā telomerase exists in human too, can lengthen telomere
- Main driver of telomere loss are Oxidation and Inflammation
- Eating vegetables, fruits, whole grains, beans, exercise, stress management ā increased telomerase activity ā some studies showed stronger impact from the diet
- Sirtuin
- enzyme to keep DNA nicely wrapped, silencing genes in that stretch of DNA (SIR: siliencing information regulator)
- Preserve dna integrity
- Improves dna repair
- Downregulates inflammation
- Maintain telomere
- 2 ways to stimulate sirtuin
- AMPK enhances sirtuin activities by increasing levels of nicotinamide adenine dinucleotide (NAD+), a cofactor for sirtuin
- Niacin (vitamin b3) is a precursor to NAD+. Vitamin d3 deficiency leads to pellagra
- STAC: sirtuin activating compounds:
- Resveratrol found in š. But resveratrol showed no impact on inflammation, cancer, cardiovascular disease, death for human
- Apple extract can reduce premature death. An apple phytonutrient phloridzin was found to boost sirtuin activities
- Glycation suppresses sirtuins
- Cellular senescence
- Hayflick limit: human cells only divide about 50 times. Then it enters the state of cellular senescence
- Helps blocking cancer by blocking proliferation of damaged cells
- But the non-dividing cells still damage surrounding tissues, releasing inflammable chemicals called senescence associated secretory phenotype (SASP)
- Exercise and caloric restriction removes senescent cells
- Quercitin (rich in onion, kale, apple) is a natural senolytic (kills senescent cells)
- Fisetin is a more potent senolytic (rich in strawberries)
- Epigenetics
- Egg cells can reverse aging otherwise babies will age before they are born
- Cloning from non-egg cells shows that cells other than egg cells can reverse aging too
- Epigenetic is what switches on and off genes
- Best known Epigenetic regulator is DNA methylation (enzymes adding methyl groups CH3- onto DNA)
- Epigenetic clock: a handful of DNA sites predictably methylate or demethylate as we age so measuring the pattern of methylation in those sites can track biological age
- Lifestyle factor most closely associated with biological aging rate: fruit and vegetable intake, carotenoid phytonutrient blood level
- Methylation silences genes. Hypomethylation (less methylation) of tumor suppressing genes is beneficial. At large scale, increase global methylation prolonged lifespan in fruit flies
- Folate (vitamin b9) can convert into methyl group. High folate diet leads to higher global methylation
- Gut bacteria bifidobacterium helps folate absorption
- Glycation
- Maillard reaction: sugar and protein react and turn brown in food during cooking
- AGE (advanced glycation end product): formed when Maillard reaction happens in body
- Hemoglobin A1c measures average blood sugar level in the ~100 days (life span of red blood cells). Hemoglobin is the protein in red blood cell that carries oxygen. It measures the % of hemoglobin thatās glycated, 5.7% is pediabetic and 6.5% is diabetic
- Hemoglobin half life ~55 days, collagen in skin half life ~15 years, collagen in spin half life ~95 years
- Glycation causes proteins to cross link and stiffens tissues including heart and arteries, increasing risk of heart disease and cancer therefore drives aging
- AGE also triggers inflammation
- At body temperature, AGE formation is slow. AGE from dietary sources also contributes to AGE in body
- Food with highest AGE: high heat treated meat. Poultry has 20% higher level than beef
- AGE formation in body is sped up by high blood sugar
- Drug Acarbose blocks starch/sugar digesting enzyme is shown to reduce blood AGE in diabetics
- Legumes reduce blood sugar response even hours after consumption, due to their fibers which feed gut bacteria, which produces short chain fatty acid that get absorbed into circulation and helps digestion
- Methylglyoxal: an inflammatory toxins formed at high blood sugar that creates AGEs. High protein and fat diet leads to higher methylglyoxal levels
- Acetones body made from keto diet can oxidize blood to a cursor to methylglyoxal
- Reduce glycemic impact (blood sugar response) in carbohydrate food: sprout, use whole grain, cook then cool to crystallize starch into resistance starch, add vinegar, eat berries/onions/cinnamon with meal, avoid eating late, walk after eat
- IGF-1
- Insulin like growth factor 1: a growth hormone
- Interference with signaling in IGF1 has shown lifespan extension in various species
- Shift bodyās priorities from growth to maintenance
- Centenarians have lower levels of IGF-1 in blood
- Taller stature correlates with shorter lifespan, mainly by increase cancer rates: each inch ā 6% increase risk of dying from cancer
- Each day 50 billion cells die and 50 billion new cells are born
- extra cell growth in adult can mean tumor
- Fasting reduces IGF-1. Protein intake far exceeding recommended amount (0.8 gram per kg of body weight) raises IGF-1. At normal dose, plant protein is safer
- Inflammation
- Part of body becomes red, warm, swollen, and painful as a reaction to tissue damage. A healing process.
- Chronic inflammation, also called metabolic inflammation, or meta-inflammation, is systemic, persistent, and nonspecific and appears to perpetuate disease.
- C Reactive protein: inflammatory marker, ideally below 1mg/L
- White blood cell is also a proxy for inflammation.
- IL-6: interleukin-6, chemical messenger used to communicate between blood cells, triggers CRP production.
- Fat cells (mostly from visceral fat, I.e. fat around organs) can spill out IL-6, as we age there are more fat cells and each fat cell spills out more IL-6
- IL-10: interleukin-10, anti-inflammatory cellular messenger
- Macrophage: a white blood cell to clean up debris. In the situation of fatty tissues expanding and dying due to oxygen deprivation, macrophage cells can accumulate and fuse into giant cells, an inflammation marker.
- Endotoxin: toxin released from bacteria. Saturated fat could potentially help endotoxins leak through gut wall into the circulation
- Location matters: poop is harmless in colon, but can be dangerous if eaten
- Endotoxin can withstand 2 hour boiling
- NEU5GC: an acid sugar in meat and dairy that causes inflammation
- Most inflammatory food: saturated fat, salt; most anti-inflammatory: turmeric, garlic, tea, fiber, flavone (high in apples, oranges, bell peppers, chamomile)
- Butyrate: short chain fatty acids created by gut microbiome, fuels of colon lining cells, signal immune system to suppress inflammatory reaction
- Butyrate also enhances secretion of IL-10
- NF-kB (Nuclear Factor kappa-light-chain-enhancer of activated B cells) is a protein complex that helps regulate the immune response to infection.
- Cruciferous vegetables inhibits NF-kB and drops CRP level and IL-6
- Oxylipin: a pro-inflammatory compound. Flaxseeds reduce oxylipin level.
- Aspirin: acetylsalicylic acid, breaks down to acetyl group and salicylic acid, the former is blood thinning by inactivating platelets, the latter is anti-inflammatory
- Oxidation
- free radical (highly reactive oxygen-based molecules, e.g. superoxide and hydrogen peroxide, as byproduct of cellular metabolism) ā pair their unmatched electrons by stealing electrons away from any molecule in their path ā damages mitochondria (major source of free radical formation) ā loss of cellular function and energy
- Heterocyclic amine: free radical formation inducing compound formed when meat is cooked
- Across species: the lower the rate of mitochondrial free radical production, the longer animals live
- Mitochondria have their own tiny loops of DNA commonly thought to code for just thirteen proteins, separate from the bulk DNA coding of the more than 20,000
- How mitochondria works: Mitochondria produce energy through cellular respiration:
- Amino acid methionine (most susceptible to oxidation) linked to higher mitochondrial free radical production
- Antioxidant supplements donāt work likely because they only contain a select few antioxidants whereas body needs hundreds of them to work together
- Non-mitochondrial DNA in cell nucleus also subject to free radical damage
- Plants create antioxidants to defend against UV induced free radicals during photosynthesis
- Protective effect from antioxidant rich food (š«) is transient and DNA vulnerability return within 2 hours
- Catalase: an enzyme to make antioxidants like glutathione. can detoxify hydrogen peroxide to water and oxygen. Fast reacting, detoxifying millions of free radicals in a second
- Nrf2: a protein in cellsā cytoplasm, normally bound to a suppressor protein, released when suppressor protein is oxidized, and can activate antioxidant response.
- Sulforaphane: a compound in cruciferous vegetables. Enables antioxidant response through activation of NRF2. Acidify raw cruciferous vegetables boost sulforaphene formation
- Oxysterol: cholesterol oxidation product, can get across blood-brain barrier. More toxic than unoxidized cholesterol
- Rancid fat: oxidized fat, accelerates atherosclerosis when made into LDL cholesterol
- Coenzyme Q10: only fat soluble antioxidant produced by human body. Centenarians have lower levels than 60 -70 year olds
- Chlorophyll rich diet helps regenerate naturally
- Selenium: a critical component of a key antioxidant enzyme. But the safety margin is narrow
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