Matt Kaeberlein, PhD discusses how improving the mechanisms of aging enhance not only support longevity, but also boost immune system health.
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Barzilai, N., Appleby, J., Austad, S., Cuervo, A., Kaeberlein, M., Gonzalez-Billault, C., Lederman, S., Stambler, I., Sierra, F. (2020). Geroscience in the Age of COVID-19 Aging and Disease 11(4), 725-729. https://dx.doi.org/10.14336/ad.2020.0629
03:45 COVID has the same age-related risk profile as Alzheimer’s, diabetes, heart disease and most cancers, in developed countries.
04:00 Your risk of a severe outcome from COVID has an age-related exponential increase.
07:03 No federal COVID funds went to the National Institute on Aging, despite the fact that age is the greatest risk factor for dying from COVID 19.
09:47 Exploring known interventions that effect biological aging in COVID may reduce risk of death and improve the effectiveness of a vaccine.
10:30 Older people, at more risk of severe outcomes from COVID 19, are the ones where a vaccine is least likely to work because they do not have a robust immune system.
18:16 Targeting the biological mechanisms of aging strengthens the immune system of older people against many illnesses.
19:44 Biological aging can be impacted significantly. With the immune system, we can probably get a 20-year restoration of function, maybe more.
21:38 The free radical theory and telomere shortening theory are true, but biological aging is far more complicated.
22:20 There are 8 – 10 hallmarks of aging. They are molecular processes that happen in most or all animals as they age that contribute to the declines in function and the diseases that go with aging.
24:06 We understand maybe 10% of aging. We have drugs and interventions that seem to have effects upon multiple hallmarks of aging. In lab studies, increase lifespan and seem to delay the functional declines.
26:26 Most of the genetic players in aging are closely connected. mTOR talks to AMP Kinase. Both of these talk to sirtuins. All of these talk to the insulin signaling pathway.
31:25 Genes that affect aging were created to make the decision between fast reproduction/low stress resistance vs slow reproduction/high stress resistance. High stress resistance is associated with slower aging. We can modify many individual genes and have effects upon aging.
32:14 Unregulated continued expression of pathways like mTOR at high levels drives aging.
33:58 The chronic expression of pro-growth pathways in different cell types is different. In dividing cells, your risk of developing cancer goes up dramatically. Lung, intestinal cells, and liver cells are highly mitotic.
35:18 In cells that are primarily post-mitotic, like most of the cells in the brain and heart, the continued expression of pro-growth pathways is associated with higher levels of oxidative stress.
35:42 High levels of oxidative stress largely from metabolic processes can cause cells to go into senescent state, where the cells give off pro-inflammatory signals.
36:10 As mammals age, there is a dramatic increase in pro-inflammatory cytokines, Inflammaging is chronic inflammation in the absence of infection, mostly driven by the accumulation of senescent cells.
37:05 Age related increase of inflammation creates an environment that permits many of the functional declines and diseases associated with aging.
37:54 In mice, if you clear senescent cells accumulated from aging, you see a dramatic reduction in inflammatory molecules and signaling, increased lifespan and functional improvements, similar to those found in the use of rapamycin.
38:12 When we treat old mice with rapamycin, in as little as 8 weeks, it turns down senescent inflammatory response.
43:03 It appears that we need appropriate cycles of growth-promoting and growth-inhibiting responses. People who exercise moderately, but regularly, are protected against diseases of aging and they tend to age better.
46:30 As animals get older, there is an increase in inflammatory signals, probably coming from the immune system. Because of a chronic inflammatory state, the immune system is no longer able to respond appropriately to challenges.
47:03 With chronic inflammation, the immune system responds inappropriately to self-antigens, thus there is an increase in autoimmunity. There is also an inability to respond to the challenges of acute infection. There is a failure to surveil cancers early.
48:20 In mice, if you take an old mouse with a poorly functioning immune system, a short-term treatment with Rapamycin will improve immune functionality similar to its youth.
49:15 Rapamycin dampens the chronic inflammatory state. Reducing this sterile inflammation may be enough to allow the immune system to function like a youthful immune system.
50:03 Vaccine response: Short term treatment with Rapamycin in mice allows old mice to respond to a vaccine like a young mouse.
50:15 Healthy older people improved their response to an influenza vaccine in 6-week clinical trials in humans using a Rapamycin derivative Everolimus/RAD001. Participants had fewer respiratory tract infections over the next year.
01:01:06 In human clinical trials, of Everolimus Rapamycin, a daily dose of one mg/day had more side effects than a once a week dose of 25 mg. mTOR inhibitors may be driven by trough levels.
01:05:15 Metformin plus Rapamycin is equally as good as Rapamycin, and may have additional benefits.
01:05:30 Rapamycin shifts metabolism away from primarily glucose-based metabolic state to utilizing alternative carbon sources, ketone bodies and fat metabolism. Dr. Kaeberlein believes that a poor glucose tolerance response is because the chronic Rapamycin makes them unused to metabolizing glucose. Metformin and Rapamycin taken seems to suppress the poor response to the glucose tolerance test.
01:09:30 People with diabetes who take Metformin live longer than people with diabetes who do not. They seem to have reduced rates of dementia, some types of cancer, and heart disease. It is unknown if non-diabetics would garner the same benefits from taking Metformin.
01:14:20 Autophagy is an important mechanism that the cell has for repairing accumulated damage. It is a cellular process to accumulate and degrade various types of molecules. High levels of autophagy are often associated with healthier aging and lifespan. High levels of autophagy are also associated with many pathological conditions.
01:17:50 You probably need cycles of productive autophagy, where you are initiating, progressing and completing the degradation/recycling.
01:26:00 You can nominate your dog to participate in the Dog Aging project. Your dog must be at least 7 years old and weigh at least 40 pounds.