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Full Notes
Richard Miller’s Background and Early Interest in Aging
- Born in Philadelphia, grew up in the northern suburbs
- Interested in science from a young age, wanted to study aging
- MD and PhD degrees from Yale in the 1970s
- Postdoc at Harvard (immunology lab) and Memorial Sloan Kettering (immunology lab)
- Set up own lab at Boston University, focusing on immunology and aging
- Moved to University of Michigan in 1990, gradually shifted focus to aging more broadly
Hayflick Limit and Telomeres
- Hayflick discovered that normal human cells divide about 50 times in tissue culture before stopping
- He believed this phenomenon was related to aging
- Many cell biologists investigated the Hayflick system under the assumption they were studying aging
- Later established that the Hayflick limit was due to the shortening of telomeres
- This led to the belief that telomeres were central to the aging process, despite evidence to the contrary
Recent Study on Hyperbaric Oxygen and Telomere Lengthening
- Study from Israel showed that volunteers exposed to hyperbaric oxygen had their telomeres lengthen
- Many people have emailed Peter about this study, asking why they are not doing hyperbaric oxygen for anti-aging benefits
Fountain of Youth and Telomeres - Telomere length is not a reliable biomarker for aging
- Telomere biology is critical in cancer biology and understanding anticancer defenses in different species
- Nobel Prize awarded for telomere elucidation, but it doesn’t fully explain aging
ITP (Interventions Testing Program) Origins
- National Aging Institute’s Huber Warner envisioned a program to test potential interventions on mice and other organisms
- Committee, including Richard Miller, developed the program focusing on mice
- Three grants awarded to Miller, David Harrison, and Randy Strong
Antiaging Medicine and Strategy
- 18 years ago, the idea of a single aging process was not widely accepted
- Seeing aging as a unitary process allows for the possibility of interrupting or slowing it down
- Caloric restriction and DAFF mutants in C. elegans provided hope for extending life and understanding aging mechanisms
Aging and Longevity Research - Aging was previously believed to be immutable and not malleable
- Researchers now focus on understanding processes that can slow aging
- Aging is caused by various factors, but key is to find processes that can postpone these factors
- Asking the right question is crucial in scientific research
Interventions Testing Program (ITP)
- Goal: Develop a fundamentally sound way of testing if a drug extends mouse lifespan
- Designed to be reliable, reproducible, and believable
- Uses a large number of mice for statistical power
- Able to detect 8–10% lifespan extension
- Run in parallel at three sites for reproducibility
- Miller lab at Michigan, Strong lab at UT San Antonio, and Harrison at Jackson labs
- Uses genetically heterogeneous mice
- Allows for more generalizable results, as it represents a more diverse population
- Reduces the chance of false positives due to specific genetic backgrounds
Genetically Heterogeneous Mice in Research
- Less than 10% of research uses genetically heterogeneous mice
- Researchers often request inbred mice, like black six mice, due to familiarity and tradition
- National Aging Institute (NIA) does not have genetically heterogeneous mice due to lack of demand
- Momentum and contracts with mouse producers make it difficult to change to genetically heterogeneous mice
ITP Drug Selection Process
- Suggestions for molecules can come from anyone
- First candidate molecules in ITP included aspirin, NDGA (nordihydroguaiaretic acid), Nitrofluorbuprofen, and one other
- Clinical data in humans can influence drug selection
- FDA approval for other indications can be a selling point for testing a drug in mice
Aspirin in ITP
- Initially showed an 8–10% increase in male mice longevity at a low dose
- Higher doses did not replicate the same results
- Limited resources prevent further testing of aspirin at different doses
Rapamycin in ITP
- Included in the second cohort of ITP in 2005
- Suggested by Dave Sharp, an expert on TOR (target of rapamycin)
Rapamycin and Longevity - Rapamycin is a drug that inhibits the function of an enzyme, leading to longevity increases in invertebrate species
- Reformulated rapamycin was given to 20-month-old mice (equivalent to 60-year-old humans) and showed a strong signal in extending lifespan
- This was surprising as caloric restriction, a known intervention for extending lifespan, typically only works when initiated earlier in life
- The rapamycin data suggests that some processes in older age are still reversible and can have a major effect on health
- This is good news for people in their 50s, 60s, and 70s who may want to take a drug to extend their lifespan
Median Survival vs. Maximum Survival
- Median survival: the age at which half of a population has died and half is still alive
- Maximum survival: the age at which the oldest individual in a population has lived (less statistically appealing)
- A better substitute is the age at which 90% of the population has lived (referred to as maximum lifespan)
- Drugs that only extend median survival but not maximum survival are less plausible as candidates for anti-aging drugs
- If a drug slows aging, it should extend the lifespan of the very oldest individuals in the treated group compared to the untreated group
Rapamycin Results
- In mice, rapamycin extended median survival by 20% in males and 13% in females
- It also extended the 90th percentile lifespan by 9% in males and 14% in females
- These results are significant as they suggest a total lifespan extension, not just an incremental increase after the drug is administered
- Rapamycin is not the only drug that works well when started at 20 months of life, but it is the only one tested so far with such a strong effect on both median and maximum survival
Acarbose in Aging - Acarbose: started at 20 months of age
- Worked half as well as when started in youth
- Statistically significant change in maximum lifespan in both sexes
- Statistically significant change in median lifespan in males
- 17 alpha estradiol: late start
- Works just as well when started at 16 or 20 months of age in males
- Late start has highly beneficial effects, similar to early start
- Rapamycin: daily dosing in food
- Inhibits mTOR complex one and complex two
- Complex one inhibition believed to provide longevity benefits
- Complex two inhibition may have negative consequences
- Intermittent strategy (e.g., weekly dosing) may be more beneficial
- Repeated rapamycin study: started at 9 months instead of 20 months
- Lower median extension, but maximum extension increased in both males and females
- Female mice had higher rapamycin blood content than male mice
- Unclear why rapamycin blood levels differ between sexes
- More research needed on drug concentrations in blood for other drugs as well
Acarbose Application
- Off-the-shelf drug typically used for diabetes
- Blocks absorption of glucose in the gut
- Well-tolerated unless taken in excessive amounts
- Used as a “cheat meal” drug to prevent glucose spikes
- Tested on mice for potential lifespan extension
- Rationale: Acarbose is similar to caloric restriction
- Results: Mice experienced weight loss or lack of weight gain
- Safety profile makes it a candidate for human clinical trials
Resveratrol
- Found in grapes and wine, gained popularity for potential anti-aging benefits
- David Sinclair’s lab at Harvard published work on resveratrol
- Mice given resveratrol experienced a statistically significant increase in median lifespan
- However, this only occurred in mice on a highly toxic diet
- No lifespan effects observed in mice not on the toxic diet
- Resveratrol was tested in the ITP due to a directive from the top
- Did not go through the usual screening process
- Dose recommendations were taken from David Sinclair and Rafa Di Cabo
Resveratrol and Longevity
- Resveratrol, a compound found in red wine, was initially believed to extend lifespan
- Studies in mice on a normal diet showed no effect on longevity
- To get the mouse dose of resveratrol, a human would have to drink 600 bottles of wine a day
Green Tea Extract and Longevity
- Green tea extract was tested for its potential to extend lifespan
- No significant effect on animal longevity was found
Methylene Blue and Longevity
- Methylene blue was tested for its potential to extend lifespan
- No significant effect on animal longevity was found
Rapamycin and Longevity
- Rapamycin has been extensively tested for its potential to extend lifespan
- It has demonstrated efficacy in extending both median and maximum lifespan in mice
17 Alpha Estradiol and Longevity
- 17 alpha estradiol is a compound similar to estrogen (17 beta estradiol) but with lower affinity for estrogen receptors
- It was tested for its potential to extend lifespan in male mice without feminizing effects
- It significantly extended median and maximum lifespan in male mice, but not in female mice
- The exact reason for the sex-specific effect is still unknown
Inbred Strains of Mice - Dozens to hundreds of inbred strains with different characteristics
- Production of new healthy pups slows down when females are 8–11 months old
- Cycles become irregular and then decrease altogether
17 Alpha Estradiol
- Obscure paper by a Swedish or Finnish group detected 17 alpha estradiol in the brain
- Isolated a receptor called the estrogen x receptor, specific for 17 alpha estradiol
- Not well known or investigated
- Unclear if it has been pursued as an investigational new drug
Salsolic Acid
- Possibly related to retinoid receptor activation
- Proposed as a way of getting at the bile acid issue
- Unclear if it is orally bioavailable or only effective in a topical form
Hydrogen Sulfide
- Jay Mitchell, a scientist who passed away, was interested in hydrogen sulfide as a controlling element in the aging process
- Suggested giving mice a drug called SG-1002 that would break down to produce hydrogen sulfide
- Results were inconclusive due to a mistake in the control group
- Repeating the experiment with the correct control group, results expected in about a year
SGLT2 Inhibitor Canagliflozin
- Widely available drug used for type 2 diabetes
- Blocks reuptake of glucose, causing more glucose to be excreted in urine
- Increased median lifespan in male mice by 14%, maximum extension of 9%
- No effect on female mice
- Unclear why there is a difference in effect between males and females
- Both male and female mice mostly die of cancer (80% of deaths)
Cancer in Mice
- Hematopoietic cancers are the leading cause of death in both male and female mice (30% of deaths)
- Different types of cancer are more prevalent in males and females
- High glucose levels may be a factor in cancer development, but the exact relationship is unclear
Metformin and the ITP
- Surprising failure of metformin in the ITP
- Rapamycin is a remarkable success story in terms of its consistency
Metformin in Aging Studies - Metformin has been tested in mice for lifespan extension
- Published twice: once by Rafa de Cabo and once by the ITP
- No significant lifespan extension in either study
- Possible reasons for Metformin’s failure in mice:
- Might be good for people, not mice
- Wrong dose used in studies
- Different dosing schedule needed
- Epidemiological paper suggests Metformin may be good for nondiabetic people
- Diabetics on Metformin had better mortality risk than nondiabetics of the same age and sex
- Observational study, not a controlled, randomized clinical trial
- TAME study aims to test Metformin in aging people
Nicotinamide Riboside (NR) in Aging Studies
- NAD and its derivatives are important in the control of aging rate
- NR is an orally bioavailable and stable form of NAD
- Tested in the ITP, but did not extend lifespan in mice
- Possible reasons: wrong dose, inconsistent changes in NAD levels in tissues
- Further studies needed to determine potential benefits of NR in aging
Drug X and Lifespan - Drug X given to mice for a month or two has positive effects without side effects
- Concerns about potential side effects if given for the entire lifespan of mice
- No drugs tested have significantly shortened lifespan, but some side effects may go unnoticed
ITP Findings
- mTOR matters less, glucose is better than more, and sex-specific steroid hormones are relevant
- However, other important takeaways include:
- Drugs can extend healthy lifespan, with significant effects
- Some drugs work even when started in middle age
- Many drugs work in one sex but not both
Model Organisms for Aging Research
- Mice are the best model organism due to their similarity to humans in terms of organs, cells, circuits, and hormones
- Other organisms like flies, worms, and marmosets also have their advantages for specific research questions
- Some work must be done in humans for obvious reasons
Rapamycin and Aging
- Rapamycin slows a wide range of age-associated changes in mice
- Mice given rapamycin had youthful organs and tendons at 22 months of age
- Slowing aging may help retard diseases that afflict members of a species, regardless of the specific cause of death
Aging and Life Extension - Importance of starting interventions early
- More opportunity to impact tendons, nephrons, cardiac myocytes, and neurons
- Evidence suggests some aspects of aging can be reversed or prevented even in late middle age
- Examples: muscle changes, grip strength, rotor rod ability, glucose tolerance
Interventions That Work (ITP) Program
- Tests various interventions to extend life in mice
- Produces studies that add to the body of knowledge on life extension
- Goal: find molecules that can extend human life by 10–15% or more
Immortality vs. Life Extension
- Immortality is not a realistic goal
- 10–15% improvement in lifespan and healthspan would be a remarkable achievement
- Focus on finding molecules that can extend life and improve healthspan
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