Purging Your Body’s Cache: senescence and senolytic therapies explained

by Mike Mutzel


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Key Timestamps:

04:35 Applying the right type of stress to your genome through the environment has a positive influence on longevity. This includes fasting and heat shock proteins.

05:07 Sauna research indicates that when your heartrate is about 140, you are in the right temperature for cardiovascular benefit and releasing heat shock proteins.

05:54 A freezer can be used for a cold bath. Jeff used it daily for 60 consecutive morning for 3 to 4 minutes at 32 degrees. It was an exploration of cold therapy’s impact upon energy, inflammation and metabolism.

08:19 With age comes an accumulation of cells that do not do what they are supposed to do, but they do not self-destruct. Senescent cell accumulation does not perform their essential functions well and they effect surrounding cells.

09:06 If you can get rid of senescent cells in your body, you get a 10 or 20% life extension, shown in nearly every model where this has been studied.

09:20 There are over the counter cheap supplements that have a senolytic effect in humans.

10:50 A senescent cell intervention study used an old leukemia drug, Dasatinib (100 mg/day), mixed with 1,000 mg OTC quercetin. When it was taken for 3 days, caused most senescent cells to go away.

15:30 Autophagy is a key hallmark of any anti-ageing program, as it has a senolytic effect. It can be achieved by fasting or activating the TOR complex.

16:32 If there is low autophagy activation in the body, lifespan is shorter. Upregulating autophagy brings greater life extension. Stressors have a powerful impact on upregulating autophagy.

17:29 When you fast, your body gets good at recycling organelles. You can go 30 – 60 days without eating.

19:10 DNA expresses itself differently when autophagy is upregulated. Science has not caught up with the ideas people have about inducing autophagy.

20:30 Stem cell activation increases in the refeeding stage after a fasting state, to replace the junk cells that were removed in autophagy.

22:15 In mice, it takes at least a 2-day water fast to induce autophagy. They have a much faster metabolism than humans. It is probably the equivalent of 4 or 5 days of a water fast in humans.

24:56 A single cell organism in the ocean 3 billion years ago could sense salt, amino acids and heat.

25:48 The TOR pathway is an amino acid sensing pathway that lets the cell know that there is food available or not. The expression of TOR leads to autophagy and potentially, unmitigated growth.

26:30 If there are a lot of nutrients in the environment, cells grow and procreate. In cancer, this is not a good thing.

27:10 If there are no nutrients in the environment, cells get good at recycling/scavenging and hunkers down to protect its DNA so it cannot break.

28:44 The antioxidant theory of ageing has been debunked.

30:20 Our modern lifestyle contributes to a high senescent cell burden.

30:33 If you are in a constant feeding state, you are storing and growing. It stimulates cancer growth through upregulation of growth hormone IGF1 and insulin.

31:00 If you activate AMPK through fasting and exercise, you signal your body to burn more fats, burn your cholesterol particles for energy, increase fatty acid oxidation, and stored sugar/glycogen becomes energy.

31:47 If you keep feeding your body glucose and excess protein, you store lipids, you get a fatty liver, fatty pancreas, insulin resistance, pre-diabetes, and diabetes. You are clogging your system with too many cells producing too much junk.

33:36 Testing can show where patients are on the longevity path: Liver enzymes,  triglycerides, inflammatory markers like the C-reactive protein test, a measure of visceral fat, insulin, C peptide, hemoglobin A1C, vLDL and Jeff looks at IGF-1 as a surrogate marker for TOR.

36:24 Overconsuming protein by over 20 to 30% in your diet, you get increased IGF-1.

36:53 There is a sweet spot for growth hormone. It is needed to build muscle. Too much may negatively impact cancer and longevity. Too little growth hormone in old age can contribute to bone loss and sarcopenia.  

37:39 A good IGF-1 level, based on Blue Zone cultures, is around 150 for mid-life. It is best captured first thing in the morning, fasted.

42:14 If you restrict methionine in mice, they live longer. Methionine is one of the main activators of TOR.

46:05 AMPK can be activated through Metformin, berberine or the Chinese herb jiaogulan.

48:02 Rapamycin works well to suppress TOR in animal models. We have no idea what the dose should be for humans. Taking too much suppresses your immune system.

48:30 Topical Rapamycin reduced fine lines, wrinkles and age spots and increased collagen in people in their 60s. Topical was about 100th of the oral dose.

51:22 NAD is the rocket fuel needed for sirtuins to do their job to protect DNA. You can ramp up NAD through fasting. It declines with the ageing process. Keto diet may increase NAD.

51:45 Fasting increases NAD, increases sirtuin activity, increases AMPK, suppresses TOR, reduces senolytic cell burden, reduces adipose and visceral fat tissue, lowers risk of cancer and heart disease.

54:38 Elissium product Basis contains pterostilbene, nicotinamide riboside (an NAD derivative which has been shown to increase mitochondrial NAD).

56:17 We don’t know if taking NAD increases lifespan or if it lowers cardio-metabolic risk.

56:52 NAD patches, intravenous NAD and subcutaneous injection are also used. There is not much research. However, people who use them tend to find increased energy.

01:00:35 Your DNA gets methylated as you age. When DNA is methylated, certain sections of DNA code are turned off and your cell does not do what it is supposed to do.

01:02:50 DNA methylation is a surrogate for the ageing process. CPG sections of the DNA are highly correlated with the ageing process if they are methylated. It is a better marker for ageing than telomeres.

01:03:59 When your DNA at the CPG sites is methylated, it is irrevocable. Smoking hyper-methylates the CPG sites of your DNA.

01:04:40 Ageing tests, from Elysium and myDNAge examine CPG sites. These tests can be used to track the efficacy of different therapies’ affect upon DNA methylation.

01:08:35 The DNA clock was reversed by 2 ½ years  after 6 months, in a study of 9 men who took HGH, DHEA, zinc, vitamin D, and Metformin.

 01:12:18 Regeneration of the thymus gland can keep your immune system strong. It largely goes dormant in your 20s. This is done with drugs that reverse engineers immunosenescence.

01:13:07 Paradoxically, studies show that increases in growth hormone leads to longevity benefits, yet high growth hormone is disaster from a longevity standpoint.

01:17:40 DHEA for men is probably safe with a recommended dosage of 25 to 50 ml. DHEA supplementation is a good idea when taking large amounts of prednisone can help to prevent loss of bone density. DHEA has a positive effect upon the immune system and helps with certain markers of cardiovascular function in men.

01:21:37 Low levels of DHEA increase your risk of all cause mortality.  DHEA, as an adrenally producing hormone, is a surrogate into the stress resiliency of an organism.

01:22:28 Surrogate markers for resilience: robust DHEA, good sleep architecture, HRV and a good balance between the sympathetic and parasympathetic nervous systems.

01:23:12 Fasting mimicking, to a higher extent than fasting, increases mucosal stem cell activity.

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