Longevity
Last Updated: 28.06.23
4 Min Read
Richard Miller, M.D., Ph.D.: The Gold Standard for Testing Longevity Drugs, the ITP
Richard Miller, a professor and Director of the Center for Aging Research, discusses the results of the Interventions Testing Programs (ITPs) animal study. The study evaluates the impact of molecules like rapamycin, metformin, and canagliflozin on aging, revealing both unexpected positive and negative findings. Attia provides insights into the outcomes and implications of these experiments.
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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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