Fight Aging!

The NIA Interventions Testing Program (ITP) is a fairly old-school effort to rigorously test all the plausible claims of modestly slowed aging in mice via pharmaceuticals, dietary supplements, and environmental factors like calorie restriction. For those of us more interested in outright rejuvenation through damage repair after the SENS model, rather than merely slowing aging a little, I think there still a number of things worth learning from the ITP results to date. For example, firstly, that almost all claims of slowed aging in mice due to supplements and drugs made in past years were artifacts or otherwise erroneous results, and vanish when evaluated with greater rigor. That suggests that any result of around 10% life extension in mice should probably be taken with a grain of salt, given that the ITP researchers have observed variance in the life spans of control mice raised in identical environments at different study sites. Secondly, that it is very hard to evaluate small differences in aging and life span. This is a part of the larger point I try to make on efforts to slow aging: that for a number of reasons it is more expensive and more challenging than attempts to produce rejuvenation by reverting the established differences between old and young tissues, such as accumulations of metabolic waste, senescent cells, and other forms of molecular damage. Rejuvenation therapies, when they work, should reliably result in larger differences in life span - there should be absolutely no ambiguity at all about the outcome.

The Interventions Testing Program (ITP) was established by the National Institute on Aging (NIA) to investigate the potential of dietary interventions to promote healthy aging. The ITP uses a four-way cross genetically heterogeneous mouse model (UM-HET3) to reduce the impact of strain-specific characteristics on outcomes. Lifespan tests are done in parallel, using the same protocol, at three independent sites to increase robustness of the findings. Population sizes are large enough that the protocol will detect a 10% change in mean lifespan, in either sex, with 80% power, pooling data from as few as two sites. Standard operating procedures were designed to maintain as much consistency as possible among the three sites, including caging, bedding, food, and light/dark cycles. Interventions for testing are proposed by the research community through an annual call-for-proposals, and proposed compounds have ranged from drugs and dietary supplements to micronutrients and metabolic intermediates.

Before the ITP embarks on testing a compound, pilot studies are done to maximize the chances of a successful test. Goals of the pilot studies include demonstrating that the compound is stable in food and that it is uniformly mixed in the food, determining blood levels after short-term treatment (bioavailability), showing evidence of an effect from the short-term treatment (bioactivity), and in some cases, testing for toxicity. The testing of rapamycin is a good case-in-point for analyzing stability of the compound in the food. Pilot analysis showed that about 85% of the rapamycin was degraded by the food preparation process, leading to the use of microencapsulation to deliver stable doses of the compound in food.

The list of all compounds tested by the ITP and in progress is on the ITP website. To date, six compounds have shown significant extension of lifespan: aspirin in males only; rapamycin in males and females (with a greater effect in females); 17αEstradiol in males only; acarbose in males and females (with a greater effect in males); nordihydroguaiaretic acid (NDGA) in males only, and protandim in males only. The positive findings illustrate some important aspects for aging interventions research. The effective interventions appear to include several disparate mechanisms, demonstrating that many cellular pathways might be exploited to influence lifespan and aging. Rapamycin modulates the nutrient-sensing pathways via its interaction with mTOR. Acarbose was anticipated to work as a caloric restriction mimetic due to its ability to reduce the rate of absorption of carbohydrates, but its mechanism of action appears more complex, since caloric restriction results in significant lifespan extension in both male and female UM-HET3 mice, while the effects of acarbose were much larger in males. Aspirin is known for its anti-inflammatory and antioxidant activities, NDGA also has anti-inflammatory and antioxidant activities, 17αEstradiol has neuro-protective properties independent of binding to the estrogen receptor, and protandim activates Nrf2 transcriptional regulator. This diverse group of interventions demonstrates the complex nature of the biology of aging.

Another major surprise is the extent of sex differences in response to the interventions. Four of the six positive interventions only worked in one sex, and the two that had an effect in both sexes showed sex-specific differences in the extent of the effect. Blood levels of a compound sometimes differed between males and females, but that did not always explain the sex difference in lifespan extension. For rapamycin, achieving approximately equivalent blood levels in males and females by treating with different doses did result in similar increases in lifespan. But for NDGA, even at doses giving similar blood levels in males and females, females still did not respond. The ITP's findings illustrate how important it is to examine the effects of interventions in both sexes and suggest that further studies on the mechanism of these sex effects may yield important insights into the underlying biology, and guidance for eventually clinical studies. Multi-site testing protocols also add value to the design because some site-to-site variation is unavoidable even with every effort made to minimize differences between sites. For example, the ITP has consistently found that control male mice at one site weigh less and live longer than the control males at the other two sites, even though each site uses the same food preparations and standardized husbandry. Positive findings replicated in different labs are inherently stronger than a finding from one lab, while disparate findings convey a valuable caution and emphasize the need for replications in other laboratories, other mouse stocks, and other drug doses.

Link: http://www.ebiomedicine.com/article/S2352-3964(16)30554-0/fulltext