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Michael R

Periodic Very-Low-Calorie Cycles: Yeast, Mice, and a Human Trial

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A hat tip to unregisted user "Cory" over in Chitchat (where there are some interviews with Longo on previous work):

 

There is a new study on periodic fasting in yeast, mice, and humans by Longo's group. The free full text is available: A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration . A few tidbits:
 

In mice, 4 days of a diet that mimics fasting (FMD), developed to minimize the burden of [prolonged fasting], decreased the size of multiple organs/systems, an effect followed upon re-feeding by an elevated number of progenitor and stem cells and regeneration. Bi-monthly FMD cycles started at middle age extended longevity, lowered visceral fat, reduced cancer incidence and skin lesions, rejuvenated the immune system, and retarded bone mineral density loss. In old mice, FMD cycles promoted hippocampal neurogenesis, lowered IGF-1 levels and PKA activity, elevated NeuroD1, and improved cognitive performance. In a pilot clinical trial, three FMD cycles decreased risk factors/biomarkers for aging, diabetes, cardiovascular disease, and cancer without major adverse effects, providing support for the use of FMDs to promote healthspan. ...

 

 

[Diets]

We developed a very low calorie/low protein fasting mimicking diet (FMD) that causes changes in markers associated with stress resistance or longevity (IGF-1, IGFBP-1, ketone bodies, and glucose) that are similar to those caused by fasting (Table S1). ... The FMD is based on a nutritional screen that identified ingredients that allow nourishment during periods of low calorie consumption (Brandhorst et al., 2013). ... The day 1 diet consists of a mix of various low-calorie broth powders, a vegetable medley powder, extra virgin olive oil, and essential fatty acids;  ... Day 1 diet contains 7.67 kJ/g (provided at ∼50% of normal daily intake; 0.46 kJ/g protein, 2.2 kJ/g carbohydrate, 5.00 kJ/g fat); ... day 2–4 diet consist of low-calorie broth powders and glycerol ... and contains 1.48 kJ/g (provided at ∼10% of normal daily intake; 0.01 kJ/g protein/fat, 1.47 kJ/g carbohydrates). An alternative FMD containing 0.26 kJ/g (0.01 kJ/g protein/fat, 0.25 kJ/g carbohydrates) was supplied for 3 days for the evaluation of adult neurogenesis. ...

 

Mice were fed the FMD starting at 16 months of age for 4 days twice a month and were fed an ad libitum diet in the period between FMD cycles. Mice ... in the FMD group lost ∼15% weight during each FMD cycle but regained most of the weight upon re-feeding (Figure S1A). ... Although FMD group mice were severely calorically restricted during the diet, they compensated for this restriction by overeating during the ad libitum period, resulting in a 14-day cumulative calorie intake equivalent to that of the ad libitum groups (Figures 1E and S1B). The average caloric intake in both cohorts increased after 25 months of age (Figure 1E) [Even tho' they both eventually began to lose weight, due to the wasting of degenerative aging -MR].
 

 

[Bloodwork]

At the end of the FMD and before re-feeding, blood glucose levels were 40% lower than those in the control diet group. Throughout the study, glucose returned to normal levels within 7 days of re-feeding (Figure S1C). [similar findings with ketones,  insulin levels , and IGF-1] ...   IGFBP-1, which inhibits IGF-1, increased 8-fold by the end of the FMD regimen, but its concentration returned to levels similar to those for ad libitum mice within 1 week of re-feeding (Figure S1G).
 

 

[Tissue Mass]

At 28 months, FMD group mice showed a trend (p = 0.06) for reduced total adipose tissue measured during the ad libitum diet period between cycles (Figure 1F). Although subcutaneous adipose tissue volume was not affected, visceral fat deposits  were reduced... Lean body mass remained similar in the two groups (Figure 1I). ...

 

At the end of the FMD, we observed a reduction in organ weight in kidneys, heart, and liver (Figures 1L–1N), but not in the lungs, spleen, and brain (Figures S1L and S1M), and a reduction in body weight (Figure S1H–S1J). The weights of these organs returned to pre-FMD levels after re-feeding.
 

[Tissue Function]

The chronic use of bi-weekly FMD cycles caused no differences in systolic and diastolic left ventricular volume, ejection fraction, and left ventricular mass, as measures of cardiac function in 25-month-old mice (Figures S1N–S1Q). Serum alanine transaminase, a liver atrophy marker, increased at the end of the FMD but returned to control levels upon re-feeding (Figure S1R). Following re-feeding, liver cells repopulated in proximity to the hepatic blood vessels (Figure 1O 4, arrow). The effect of the FMD on hepatic regeneration 24 hr post re-feeding was supported by a 10-fold induction of a marker for hepatic cellular proliferation (Ki67), which is absent in G0 cells (Figures 1P and S1S). Ki67 remained elevated for at least 3 days post-FMD.

 

Renal function, assessed by serum creatinine and blood urea nitrogen measurements, revealed no alterations ... Renal histology, to evaluate glomerular and interstitial fibrosis, also showed no change in the number of sclerotic glomeruli (Figure S1V). These data are supportive of hepatic regeneration as a consequence of FMD-re-feeding cycles and with the absence either liver or kidney toxicity even after 4 months on the FMD.

[Muscle Regenerative Capacity]
Postnatal growth and regeneration of the skeletal muscle requires myogenic precursors termed satellite cells (Sinha et al., 2014). Pax7 expression is critical for satellite cell biogenesis, survival, and self-renewal (Olguin et al., 2007), whereas the myogenic transcription factors MyoD and MyoG promote muscle development and differentiation (Perry and Rudnick, 2000). Pax7 upregulation and reduced MyoD expression is observed in undifferentiated myogenic cells (Olguin et al., 2007). An age-dependent decline in Pax7 (Figure 1Q) and MyoD (and less pronounced in MyoG) was detected in 20-month-old mice (Figures S1W and S1X).

 

At the end of the FMD, Pax7 expression was reduced by ∼40% compared to that in control animals. A similar trend was also observed for MyoG (p = 0.074). 1 week after re-feeding, Pax7 expression in 20-month-old FMD group animals reached levels similar to those in 12-month-old ad libitum fed animals (Figure 1Q). By contrast, MyoD expression in old animals was not altered by the FMD (Figures S1W and S1X). Taken together, these changes are consistent with muscle regeneration and rejuvenation upon re-feeding, although further analyses similar to those performed for the hematopoietic and nervous systems (see below) are necessary to confirm this hypothesis and determine the mechanisms responsible for it. ...

[Bones]
Tissue mineral density in both femora decreased in 28-month-old C57BL/6 mice compared to that in 12-month-old mice (Figure 1S), in agreement with previously published data (Shen et al., 2011). At 28 months, femoral bone density was higher in the FMD group compared to that in the control diet group (Figure 1S), indicating that FMD cycles either attenuated age-dependent bone mineral density loss or induced bone regeneration.

 

Cancer and Inflammation
... Necropsies indicated a 45% reduction in neoplasia incidence in the FMD group ...(Figure 2I). By the end of life, lymphomas affected ∼67% of control mice, but only ∼40% of mice in the FMD group (Figure 2J), although the FMD did not cause a shift in the type of neoplasms. Notably, the FMD also postponed the occurrence of neoplasm-related deaths by over 3 months, from 25.3 ± 0.66 months in the controls to 28.8 ± 0.72 months of age in the FMD cohort (p = 0.003) (Figure 2K). Furthermore, necropsies revealed that the number of animals with multiple (3 or more) abnormal lesions was more than 3-fold higher in the control than in the FMD group (p = 0.0067; Fisher’s exact test) (Figure 2L). Therefore, the cycles of the FMD started at middle age reduced tumor incidence, delayed their onset, and caused a major reduction in the number of lesions, which may reflect a general switch from malignant to benign tumors.

Inflammation can play a key role in the development of many age-related diseases including cancer (Bartke et al., 2013, Morgan et al., 2007). Pathological analysis showed a reduced number of tissues with inflammation (e.g., reactive lymph nodes or chronic hepatic inflammation, Table S2) in the FMD mice compared to those in the control group (Figure 2M). One of the inflammatory conditions observed in C57BL/6 mice is severe ulcerating dermatitis (Figure 2N). Control animals had an ∼20% incidence of progressing skin lesions that required animal sacrifice in contrast to the ∼10% incidence for mice in the FMD-fed group. ...

 

 

Immunosenescence and Bone-Marrow-Derived Stem and Progenitor Cells
... “immunosenescence” [is] manifested as a shift in the lymphoid-to-myeloid ratio [ie, fewer bone marrow stem cells biased toward forming T-cells, B-cells, and natural killercells, and more that are biased to form red blood cells and other white blood cells -MR] and elevated incidence of anemia and myeloid malignancies ... FMD causes a rejuvenation of the blood profile (Figures 2O–2S; Figures S2E–S2R; Table S3) and a reversal of the age-dependent decline in the lymphoid-to-myeloid ratio (L/M) (Figure 2 P), as well as of the age-dependent decline in platelets, and hemoglobin (Figures 2Q–2S). Also, 4 months of FMD cycles resulted in an increase in red blood cell count and hemoglobin levels compared to baseline ...

Among the bone marrow-derived stem cells, hematopoietic stem cells and mesenchymal stem cells represent a potential source for adult tissue and organ regeneration. ... The number of HSPCs [haematopoietic stem cells] is known to increase with age, possibly to compensate for a reduction in function (Geiger and Van Zant, 2002, Morrison et al., 1996) ... [while] the number of MSPCs [mesenchymal stem cells] declines with age ...The number of MSPCs increased 5-fold in the FMD cohort (469.8 ± 179.5 FMD versus 95.5 ± 16.7 CTRL; Figures 2T and S2W), and that of BrdU+ [actively-proliferating] MSPCs increased by 45-fold in FMD-treated mice (69.8 ± 34.0 FMD versus 1.5 ± 0.6 CTRL) (Figures 2T and S2X). Taken together, these data suggest that cycles of FMD are effective in promoting increases in hematopoietic and mesenchymal stem and progenitor cells, which are likely to contribute to the regeneration of various cell types/systems. ...

 

Motor Coordination, Memory, and Neurogenesis
... 23-month-old mice fed the FMD every 2 weeks (FMD-RF, tested 1 week after resuming the normal diet) were able to stay longer on the rotarod than mice in the control diet group (Figure 3A). We also assessed motor learning ability by examining performance improvement during subsequent trials. The mice from the FMD-RF group performed consistently better by staying on the accelerating rod longer than mice on the ad libitum diet, although the rate of learning was similar in the two groups (sessions 2–5; Figure 3B). Mouse body weight and best rotarod performance were negatively associated (Pearson correlation coefficient r = −0.46; p = 0.005). When corrected for weight, rotarod performance improvement was no longer significant (p = 0.34; data not shown), indicating that the FMD mice [merely] benefit from the fat loss.

To test the effect of the diet on cognitive performance, we carried out working memory tests (Beninger et al., 1986) at 23 months of age (Figure 3C). Mice in the FMD cohort displayed enhanced spontaneous alternating behavior compared to control mice, with no difference in the total number of arm entries (a measure of activity) (Figure S3A). Short-term cognitive performance and context-dependent memory were assessed with the novel object recognition test (Figures 3D and 3E) (Bernabeu et al., 1995). FMD mice had a higher recognition index (RI = 0.60) compared to controls (RI = 0.52; p < 0.01) (Figure 3D). An increase in exploration time was observed for the FMD mice for the new object, while the total exploration time remained the same (13.6 ± 0.9 CTRL versus 13.4 ± 0.9 FMD-RF), suggesting enhanced short-term cognitive performance, not general activity (Figure 3E; Figure S3B).

As a measure of long-term memory, we measured spatial learning and memory using the Barnes maze: a hippocampus-dependent cognitive task requiring spatial reference memory to locate a unique escape box by learning and memorizing visual clues (Figures 3F–3K) (Barnes, 1988). During the 7-day training period, FMD mice performed better with regard to errors, deviation, latency, and success rate compared to controls (Figures 3F–3I). In the retention test, the FMD group displayed better memory indicated by reduced deviation at day 14 (Figure 3G). Deviation of control diet mice at day 14 was similar to that at day 1, indicating that these mice did not remember the box location they had learned by day 7. Improvements in the search strategy, including the shifting from a random and serial search strategy to spatial strategies, were observed for the FMD, but not the control diet group after days 3–4 (Figures 3J and 3K). Together, the behavioral tests suggests that FMD cycles improve motor learning and hippocampus-dependent short- and long-term memory in old animals. ...

To determine whether the diet affected neurogenesis, we measured BrdU incorporation [a measure of actively-proliferating cells] in the subgranular layer [one of the two neurogenic areas of the brain] of control mice  ... we observed an age-dependent decline in BrdU incorporation in the dentate gyrus (... [There was] an increased proliferation of immature neurons in the FMD group compared to that in controls (Figures 4C–4E). To investigate mechanisms of FMD-induced neurogenesis, we fed 6-month-old [early-adult] mice, in which cellular proliferation in the dentate gyrus is reduced by more than 50% compared to that in 8-week-old ["teenaged"] mice (Figure 4B), with a single cycle of the FMD. After 72 hr on the FMD, we observed a reduction in circulating (Figure S1E) and hippocampal IGF-1 (Figure 4F) but increased IGF-1 receptor mRNA expression in the dentate gyrus region of the hippocampal formation (Figure 4G). Micro-dissected dentate gyrus-enriched samples from FMD mice displayed a major reduction in PKA activity (Figure 4H) and a 2-fold induction in the expression of NeuroD1 (Figure 4I), a transcription factor important for neuronal protection and differentiation (Gao et al., 2009). Similarly, a single cycle of the FMD increased radial glia-like cells (type I) and non-radial precursor (type II) neural stem cells (Figures S4B, S4C, S4F, and S4G), immature neurons (Figures S4D and S4I–S4Q), and the dendrite-covered area (Figures S4E and S4H) in CD-1 mice.

These results in two genetic backgrounds indicate that the FMD promotes neurogenesis in adult mice. Notably, the brain did not undergo a measurable weight reduction during the FMD, indicating that regeneration can also occur independently of the organ size increase after refeeding. Thus, we hypothesize that alterations in circulating factors, such as the reduction in IGF-1 levels and PKA signaling, can induce pro-regenerative changes that are both dependent and independent of the major cell proliferation that occurs during re-feeding, in agreement with our previous finding in bone marrow and blood cells (Cheng et al., 2014). Most likely, the increase in IGF-1 and PKA after refeeding also contributes to the proliferative and regenerative process, raising the possibility that both low and high levels of these proteins can promote regeneration depending on the timing of their expression. Alternatively, the FMD may increase survival of newly differentiated neurons, as observed in the dentate gyrus of alternate day-fed rodents...

 

FMD and Lifespan
Control mice had a median lifespan of 25.5 months (Figure 5A), which was extended to 28.3 months (11% extension) in the FMD group (p < 0.01). [This actually means that their controls were somewhat short-lived, and even their FMD animals lived less long than normal, healthy, well-husbanded AL mice should have, albeit they did live longer than their controls -MR]. The FMD showed an 18% extension effect at the 75% survival point, but only a 7.6% extension effect on the 25% survival point and no effect on maximum lifespan (Figures 5A and 5B), indicating that at very advanced ages the 4-day FMD may be beneficial for certain aspects and detrimental for others. Further analysis indicated that many deaths at very old ages occurred during or shortly (within 3 days) after completion of the FMD cycle (Figure 5E, asterisk).

 

[Alternate Protocol] Based on this observation, at 26.5 months we shortened the FMD diet from 4 to 3 days and halted the FMD diet completely at 29.5 months. Analyses of the data indicate that whereas the shortening of the FMD from 4 to 3 days was associated with reduced mortality rates between 26.5 and 29.5 months, the halting of the FMD diet at 29.5 months did not reduce mortality further (Figure 5D). These results suggest that FMD cycles can have a potent effect on lifespan and healthspan, but, at least for very old mice, a less-severe (3 versus 4 days) low-calorie and low-protein diet may be preferable to continue to provide beneficial effects while minimizing malnourishment, in agreement with our recent work demonstrating opposite roles of high protein intake on health/mortality in mice and humans of middle to old and very old ages (Levine et al., 2014).

 

Periodic FMD in a Pilot Randomized Clinical Trial
Markers of Aging and Diseases
To evaluate the feasibility and potential impact of a periodic low-protein and low-calorie FMD in humans, we conducted a pilot clinical trial in generally healthy adults. The components and levels of micro- and macro-nutrients in the human FMD were selected based on their ability to reduce IGF-1, increase IGFBP-1, reduce glucose, increase ketone bodies, maximize nourishment, and minimize adverse effects (Figure 6) in agreement with the FMD’s effects in mice ...

 

The human fasting mimicking diet (FMD) program is a plant-based diet program designed to attain fasting-like effects while providing micronutrient nourishment (vitamins, minerals, etc.) and minimize the burden of fasting. It comprises proprietary vegetable-based soups, energy bars, energy drinks, chip snacks, chamomile flower tea, and a vegetable supplement formula tablet (Table S4).

 

Table S4 Caloric content of the human FMD regimen.
 
""                        "Day 1"    "Day 2- 5"
-------------------------------------------
"Calories"               "~1090"    "~725"
"Protein (%)"                 "10"    "9"
"Fat (%)"                      "56"    "44"
"Carbohydrates (%)"    "34"    "47"

 

[This appears likely to be Longo's patented line of food bars and other proprietary "fasting-mimicking" foods:

 

 

The FMD diet provides high micronutrient content mostly (i.e., greater than 50 percent by weight) from natural sources including: Kale, Cashews, Yellow Bell Pepper, Onion, Lemon Juice, Yeast, Turmeric. Mushroom, Carrot, Olive Oil, Beet Juice, Spinach, Tomato, Collard, Nettle, Thyme, Salt, Pepper, Vitamin B12 (Cyanocobalamin), Beets, Butternut Squash, Oregano, Tomato Juice, Orange Juice, Celery, Romaine Lettuce, Cumin, Orange Rind, Citric Acid, Nutmeg, Cloves, and combinations thereof. ...  FMD includes the following micronutrients (at least 95% non-animal based): over 5,000 IU of vitamin A per day (days 1-5); 60-240 mg of vitamin C per day (days 1-5); 400-800 mg of Calcium per day (days 1-5); 7.2-14.4 mg of Iron per day (days 1-5); 200-400 mg of Magnesium per day (days 1-5); 1-2 mg of copper per day (days 1-5); 1-2 mg of Manganese per day (days 1-5); 3.5-7 mcg of Selenium per day (days 1-5); 2-4 mg of Vitamin B1 per day (days 1-5); 2-4 mg of Vitamin B2 per day (days 1-5); 20-30 mg of Vitamin B3 per day (days 1-5); 1-1.5 mg of Vitamin B5 per day (days 1-5); 2-4 mg of Vitamin B6 per day (days 1-5); 240-480 mcg of Vitamin B9 per day (days 1-5); 600-1000 IU of Vitamin D per day (days 1-5); 14-30 mg of Vitamin E per day (days 1-5); over 80 mcg of Vitamin K per day (days 1-5); 16-25 mcg Vitamin B12 are provided during the entire 5-day period; 600 mg of Docosahexaenoic acid (DHA, algae-derived) are provided during the entire 5-day period.

 

Hat tip to Reddit user shrillthrill for pointing this out -MR]

 

 Subjects were randomized either to the FMD for 5 days every month for 3 months (3 cycles) or to a control group in which they continued to consume their normal diet (Figure 6A). Subjects were asked to resume their normal diet after the FMD period and were asked to not implement any changes in their dietary or exercise habits. ... [Results below are for compliant completers only. People on the FMD were a bit older, and men were older than women on BOTH diets] ...

 

For the FMD group, the follow-up examinations occurred before resuming normal food intake at the end of the first FMD cycle (FMD) and after 5–8 days of normal dieting following the third FMD cycle (FMD-RF, Figure 6A). ... FMD group was highly compliant and generally did not consume foods not included in the FMD box provided to them. ... Adverse effects were higher after completion of the first FMD cycle compared to those during the second and third FMD cycles. However, the average reported severity of the side effects was very low and below “mild” (<1 on a scale of 1–5).

[Bloodwork]

In the FMD subjects, fasting blood glucose levels were reduced by 11.3% ± 2.3% (p < 0.001; FMD) and remained 5.9% ± 2.1% lower than baseline levels after resuming the normal diet following the third FMD cycle (p < 0.05; Figure 6B). Serum ketone bodies increased 3.7-fold at the end of the FMD regimen (p < 0.001) and returned to baseline levels following normal food intake (Figure 6C). Circulating IGF-1 was reduced by ∼24% by the end of the FMD period (p < 0.001) and remained ∼15% lower after resuming the normal diet (p < 0.01; Figure 6D). IGFBP-1 was increased 1.5-fold at the end of the FMD regimen (p < 0.01) and returned to baseline levels following normal food intake ...

A complete metabolic panel (Figures S5E–S5L) indicated no persistent metabolic changes due to the FMD except for lowered bilirubin and alkaline phosphatase following the return to the normal diet. ...

 

 CRP levels were reduced by the FMD cycles. ...

 

Weight, Abdominal Fat, Lean Body Mass, and Metabolic Markers
...The FMD resulted in a 3% reduction in body weight (3.1% ± 0.3%; p < 0.001; Figure 6F) that remained lower at the completion of the study (p < 0.01; Figure 6F). Trunk fat percentage... showed [only] a trend (p = 0.1) for reduction ... while the relative lean body mass adjusted for body weight was increased after completion of 3 cycles (Figure 6H), indicating that fat loss accounts for most of the weight loss. Pelvis bone mineral density was not affected by the FMD (Figure S5D).

Regenerative Markers
...  Although not significant, the percentage of MSPC in the peripheral blood mono-nucleated cell population showed a trend (p = 0.1) to increase from 0.15 ± 0.1 at baseline to 1.06 ± 0.6 at the end of FMD, with a subsequent return to baseline levels after re-feeding (0.27 ± 0.2). A larger randomized trial will be required to determine whether the number of specific populations of stem cells is in fact elevated by the FMD in humans.

 

A very nicely put-together combination of studies. However, contrary to what the popular press (and it seems even Longo himself) is saying about the study, it confirms yet again that fasting regimens don't deliver life extension absent an overall reduction in Calories, despite significant and translatable metabolic changes, and some pretty clear evidence of improved health on several parameters.

 

Normally, of course, that forces the question "so what's killing all these healthy mice?", but in this case we apparently know: at older ages, the animals don't tolerate the very fasting cycles that have given them much of their improved health, and it triggers their death. And note that in the FMD, even the "fasting" days still contained some energy, so this wasn't as severe a shock as a periodic water or juice fast. Indeed, it was a concern that just this kind of problem might be leading to false negatives in adult-onset CR studies that led Weindruch and Walford, in their seminal adult-onset studies of "regular daily CR," to institute CR gradually instead of all at once as is usually done without problem in juvenile mice (and to modify the diet to include a full regimen of micronutrients, protein, and essential fat at fewer Calories, instead of just feeding them half of the AL diet as had been successfully done with juveniles). Using such a protocol gave them the first clear-cut evidence that CR extends lifespan in early-adult mice — an effect later replicated in progressively older animals, including Spindler's study in "early-old" (50-60 mouse years) animals.

This might argue that even if some modified fasting regimen works well for you in mid-adulthood, you'd have to gradually shift into "regular daily CR" as you age to reap life extension benefits and avoid the metabolic shock of the super-low-Calorie periods. However, that, of course, remains to be proven -- in mice ;) .

Edited by Michael R
Sharper emphasis

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Very interesting, Michael!  And thanks much for your helpful bracketed explanations and evaluations.

 

Longo's research is, indeed, fascinating.  Particularly interesting may be his hope to develop a drug that partially inhibits IGF1 -- when and if such a drug is developed, it will be interesting to see if it actually extends maximum and/or average life span in treated rodents.

 

  -- Saul

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Michael,

 

Thanks for the useful annotations and summary. As I noted on another thread, I'm currently doing an IF diet, and am wondering whether 3 days twice a month might be easier, and perhaps more effective, than my low-calorie day every third day plan. It's frustrating that there isn't more research to remove the huge amount of guesswork involved in these decisions about non-standard restricted eating (well, there's a lot of guesswork involved in normal, daily CR, as well, of course).

 

Saul, I'm not subscribed to Science News. When the article comes out, could you let us know any useful tidbits?

 

Zeta

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Michael Rae wrote:

 

 

A very nicely put-together combination of studies. However, contrary to what the popular press (and it seems even Longo himself) is saying about the study, it confirms yet again that fasting regimens don't deliver life extension absent an overall reduction in Calories, despite significant and translatable metabolic changes, and some pretty clear evidence of improved health on several parameters

 

Granted they didn't find that intermittent fasting extended "maximum" lifespan (age of death of the oldest few mice) nor slow aging in the technical, academic sense (increase in mortality doubling time), but it did do a pretty impressive job of squaring the mortality curve and thereby increasing mean lifespan, and lifespan of the longest-lived 25%.

 

Here is the mortality graph from figure 5 of the paper:

 

Z3TqT13.jpg

 

Five of the 29 mice (17%) on the intermittent fasting diet died within 3 days of one of the fasting periods during the 26th month of the experiment. If they had backed off the severity / length of the fasting period a month earlier, the difference in the survival curves for the two groups would have been even more impressive.

 

Given the uncertainty about the efficacy of CR in humans, extending the lifespan of the mean and longest-lived 25% seems like a pretty attractive outcome.

 

BTW, if we scale the lifespan of these mice to humans (assuming a maximum lifespan of about 95 for a small cohort of humans) - that would equate to backing off the severe IF regime at round age 70 to avoid the deleterious effects of stress and possible malnutrition.

 

--Dean

Edited by Dean Pomerleau

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All:
 

Michael Rae wrote:

A very nicely put-together combination of studies. However, contrary to what the popular press (and it seems even Longo himself) is saying about the study, it confirms yet again that fasting regimens don't deliver life extension absent an overall reduction in Calories, despite significant and translatable metabolic changes, and some pretty clear evidence of improved health on several parameters


Granted they didn't find that intermittent fasting extended "maximum" lifespan (age of death of the oldest few mice) nor slow aging in the technical, academic sense (increase in mortality doubling time), but it did do a pretty impressive job of squaring the mortality curve and thereby increasing mean lifespan, and lifespan of the longest-lived 25%.

Here is the mortality graph from figure 5 of the paper:

Z3TqT13.jpg

Well, there's two things to note here. First, look visually at the survival curve of the controls. It's decidedly non-rectangular: that is, there were a substantial number of relatively early deaths that drag out the mortality curve, instead of the more clear-cut pattern of few or no early deaths followed by a "knee" in the survival curve that you see really well-conducted animal lifespan studies, such as those by Walford, Weindruch, Spindler, or Miller. In such studies, both the controls and the CR (or rapamycin, or whatever effective anti-aging intervention you use) exhibit nice rectangular curves: the difference is that the slow-aging group's curve is shifted to the right:
 

image003.gif


Instead, in this paper, you see a ragged falloff of the control animals, and a somewhat squarer but still suboptimal survival curve in the intervention group. This isn't a sign of a good intervention: it's a sign of sickly controls. I alluded to this in my original post: "[This actually means that their controls were somewhat short-lived, and even their FMD animals lived less long than normal, healthy, well-husbanded AL mice should have, albeit they did live longer than their controls -MR]." Those numbers correspond to 775 d mean and 1015 d maximum LS in controls, and 860 and 1049 d respectively in FMD, whereas (as I have hammered home repeatedly in my ≈18 y participation in online discussion forums about life extension) the numbers for normal, healthy, nonobese, non-genetically-messed-up, non-toxin-fed mice should be ≈900 and ≈1100 d, respectively.

Even the "extension" of mean LS is not really an extension, therefore: the FMD animals just suffered a bit less premature mortality, leading to an 11% closer-to-normal mean LS. IAC, the effect is against the shortest-living animals in a short-living control group. That may represent something useful in the context of the average (or slightly below-average) American's disease risk, due to smoking, overweight, poor overall diet, inactivity, and inadequate access to healthcare: it doesn't represent a health-conscious person with education and insurance.

I can't say for sure why these early deaths occurred, but there's a pretty obvious culprit. It's not the genetics: they used the ol' reliable C57BL/6 mice. But I'd say there's good reason to think it's the classic "fat rats" problem: all they say about food intake is "Mice were fed ad libitum with irradiated TD.7912 rodent chow (Harlan Teklad) containing 15.69 kJ/g of digestible energy (3.92 kJ/g animal-based protein, 9.1 kJ/g carbohydrate, 2.67 kJ/g fat)", which absent additional precaution means the animals spent all day snacking their way into metabolic morbidity. As Dean knows but many people unfamiliar with the CR research may not, in properly-done CR studies, the ad libitum controls aren't literally fed "ad libitum," but are "restricted" by ≈10-15% from what they'd eat if allowed to just sit around stuffing their faces, exactly to avoid confounding by obesity-avoidance. So the FMD helped to avoid excessive mortality from metabolically-morbid mice with nothing better to do all day than get fat and sick.

Again, this suggests FMD is useful for people with metabolic syndrome or diabetes, and maybe people who are headed in that way; it doesn't suggest anything useful to a person who eats hir fruits and vegetables, avoids saturated fat and sugar, gets some exercise, and doesn't smoke.
 

Five of the 29 mice (17%) on the intermittent fasting diet died within 3 days of one of the fasting periods during the 26th month of the experiment. If they had backed off the severity / length of the fasting period a month earlier, the difference in the survival curves for the two groups would have been even more impressive.


But they tried this, and it didn't work. As I quoted from the paper in my original post:
 

Based on this observation, at 26.5 months we shortened the FMD diet from 4 to 3 days and halted the FMD diet completely at 29.5 months. Analyses of the data indicate that whereas the shortening of the FMD from 4 to 3 days was associated with reduced mortality rates between 26.5 and 29.5 months, the halting of the FMD diet at 29.5 months did not reduce mortality further (Figure 5D). These results suggest that FMD cycles can have a potent effect on lifespan and healthspan, but, at least for very old mice, a less-severe (3 versus 4 days) low-calorie and low-protein diet may be preferable to continue to provide beneficial effects while minimizing malnourishment, in agreement with our recent work demonstrating opposite roles of high protein intake on health/mortality in mice and humans of middle to old and very old ages (Levine et al., 2014).


And as I therefore concluded my post:
 

Normally, of course, that forces the question "so what's killing all these healthy mice?", but in this case we apparently know: at older ages, the animals don't tolerate the very fasting cycles that have given them much of their improved health, and it triggers their death. And note that in the FMD, even the "fasting" days still contained some energy, so this wasn't as severe a shock as a periodic water or juice fast. Indeed, it was a concern that just this kind of problem might be leading to false negatives in adult-onset CR studies that led Weindruch and Walford, in their seminal adult-onset studies of "regular daily CR," to institute CR gradually instead of all at once as is usually done without problem in juvenile mice (and to modify the diet to include a full regimen of micronutrients, protein, and essential fat at fewer Calories, instead of just feeding them half of the AL diet as had been successfully done with juveniles). Using such a protocol gave them the first clear-cut evidence that CR extends lifespan in early-adult mice — an effect later replicated in progressively older animals, including Spindler's study in "early-old" (50-60 mouse years) animals.

This might argue that even if some modified fasting regimen works well for you in mid-adulthood, you'd have to gradually shift into "regular daily CR" as you age to reap life extension benefits and avoid the metabolic shock of the super-low-Calorie periods. However, that, of course, remains to be proven -- in mice ;) .


Most people reading this post — and unfortunately, most people even getting started on CR or considering FMD — are already middle-aged or older, so the question is kind of moot.

If I am asked, "is FMD better than nothing?" I'd say probably yes: if you're just not going to do CR, and especially if you feel better, lose some excess weight, or see improvements in your bloodwork after going on FMD (though you should make sure to get data midway between low-Calorie periods, and not just during or the day after those periods), all power to you. But the impression that these effects are remarkable or anywhere near those of regular, daily CR is way off the mark.
 

I'm currently doing an IF diet, and am wondering whether 3 days twice a month might be easier, and perhaps more effective, than my low-calorie day every third day plan.


I'd say based on past experience with classic EOD and IF diets, your every-third-day plan is probably more effective. But it's quite clear in all of this that it's the net effect on Calorie intake that matters. No net CR in FMD = no effect on aging rate.
 

I'm not subscribed to Science News. When the article comes out, could you let us know any useful tidbits?


As people getting Al Pater’s feed will have seen, it’s now available in the Archives (when they’re up, as they are at the moment). The most notable highlight:
 

For nerve cell growth, this study hints that the rest periods between dieting bouts, not the time spent cutting calories, is what’s important, says neuroscientist Mark Mattson of the National Institute on Aging in Baltimore. In his own work, Mattson has found that fasting can yield nerve cell regeneration in the mouse brain, but his mice endured a much stricter fasting regimen of little to no food every other day. The new research shows the importance of the refeeding and recovery periods, he says.


It also says that "Information about the exact foods that participants ate is proprietary," but see my original post: patent documents appear to disclose that information. IAC, I expect that any well-designed diet with a similar protocol (such as Dr. Michael Mosley's The Fast Diet or The Every-Other-Day Diet by CR and IF researcher Dr. Krista Varady) would exert similar effects.

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Michael,

 

Thanks for your additional insights. Regarding backing off the severe fasting protocol for the aged mice to avoid mortality, I should have said if they had backed off a month earlier, at the beginning of month 25, before the large die off in the FMD group coincident with the end of the fasting period, the mortality curve for the FMD mice might have looked significantly better. But obviously hindsight is always 20/20.

 

I agree with you that in mice, IF without a net decrease in calories doesn't appear to result in the classic (max) lifespan extension observed in mice subject to daily CR, and the average lifespan extension in this study can potentially be explained as a result of simple obesity avoidance.

 

Dean

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Dean and Michael, thanks for the interesting posts.

 

[suffering a bit less premature mortality] may represent something useful in the context of the average (or slightly below-average) American's disease risk, due to smoking, overweight, poor overall diet, inactivity, and inadequate access to healthcare: it doesn't represent a health-conscious person with education and insurance.

 
You mean a health-conscious, educated person and with healthcare resources (via insurance or whatever it be) who's healthy. A frequent refrain around here is: ~"It only works for unhealthy or genetically screwed up rodents". Well, a lot of us are unhealthy or genetically screwed up.
 

 

 I'm currently doing an IF diet, and am wondering whether 3 days twice a month might be easier, and perhaps more effective, than my low-calorie day every third day plan.


I'd say based on past experience with classic EOD and IF diets, your every-third-day plan is probably more effective. But it's quite clear in all of this that it's the net effect on Calorie intake that matters. No net CR in FMD = no effect on aging rate.

 

You mean research experience, or my own personal experience (which you may know about), or your own experience?

 

Zeta

 

P.S. Archives now down (arg...), so I can't read the article, but I will look for it later.

 

 

 

 

Edited by Zeta

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 But the impression that these effects [of intermittent fasting] are remarkable or anywhere near those of regular, daily CR is way off the mark.

 

Michael,

 

I grant you this statement looks to be true for mice - IF does not appear to provide the slowing of aging benefits provided by CR.

 

But given the uncertainty about whether CR benefits in rodents will translate to people (which you acknowledge in your analysis [1] of the disappointing results of the Wisconsin & NIA CR primate studies), and given the fact that the primary markers we look for as indicators of 'successful' CR in people (reduced IGF-1, improved lipids, improved fasting glucose, reduced inflammation) also appear to result from IF (as this study illustrates), I don't see how the apparent certainty of your statement above ("...anywhere near..." & "...way off the mark") squares with the human evidence available.

 

Put another way, if we can't rule out that the benefits of CR for people may be largely a result of the health benefits of obesity avoidance, which you suggest in [1] as a reasonable way of interpreting the primate CR data in the section on "diminishing returns", and IF can accomplish the same, how can you be so certain of the inferiority of IF to CR in humans?

 

--Dean

 

[1]  http://sens.org/research/research-blog/cr-nonhuman-primates-muddle-monkeys-men-and-mimetics

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All:

 

 

[suffering a bit less premature mortality] may represent something useful in the context of the average (or slightly below-average) American's disease risk, due to smoking, overweight, poor overall diet, inactivity, and inadequate access to healthcare: it doesn't represent a health-conscious person with education and insurance.

You mean a health-conscious, educated person and with healthcare resources (via insurance or whatever it be) who's healthy. A frequent refrain around here is: ~"It only works for unhealthy or genetically screwed up rodents". Well, a lot of us are unhealthy or genetically screwed up.

 

While in no way dismissing the challenges faced by those who face specific and difficult-to-treat or unmodifiable disease states or risk factors, I actually wouldn't say "a lot of us" are — but that's really a side issue. The reasons that I'm drawing the distinction are twofold. First, the whole point of the FMD — and all the enthusiasm around various IF/EOD approaches — is that they are proposed to deliver the almost unique anti-aging benefits of CR with less hunger and/or hassle and/or side-effects. If FMD is really just correcting for the specific health problems of a particular mouse strain or laboratory husbandry practices, it doesn't meet the bar.

 

Second: of course, this is the CR Society Forum, not the "discuss every therapy for every health condition that plagues human life" Forum. The fact that a diet is good for coeliac, or diabetes, or phenylketonuria, or multiple sclerosis isn't a good reason to be discussing it here.

 

Third, even if one is either sick or genetically vulnerable to some illness, one should have some good reason to think that the disease model and the intervention is relevant to oneself before chasing after it. Cases like this are only relevant if you're actually suffering with problems analogous to those of these mice: in this case, if you're eating too much of a less-than-ideal diet and sitting on your ass all day. And if that's your problem, the most obvious and evidence-based thing to do is not FMD, but to eat a healthier diet, cut a few Calories, and get off of your ass.

 

If, on the other hand, one is sick for entirely different reasons (and certainly if those problems are genetic), then there's again no reason to pay any attention to them, any more than a heart disease patient should consider taking a therapy because it does wonders for leukaemia patients.

 

By contrast, the benefits of CR (or other interventions that retard aging in mammals) — if it's translatable! — are of universal relevance, because we're all aging. And so far, CR remains the most powerful and most robust intervention available to do that in mammals — and most of the alternatives aren't practicable (genetic modifications, impossible levels of methionine restriction, rapamycin).

 

 

 

I'm currently doing an IF diet, and am wondering whether 3 days twice a month might be easier, and perhaps more effective, than my low-calorie day every third day plan.

I'd say based on past experience with classic EOD and IF diets, your every-third-day plan is probably more effective. But it's quite clear in all of this that it's the net effect on Calorie intake that matters. No net CR in FMD = no effect on aging rate.

 

You mean research experience, or my own personal experience (which you may know about), or your own experience?

 

Sorry: research experience.

 

 

But the impression that these effects [of intermittent fasting] are remarkable or anywhere near those of regular, daily CR is way off the mark.

I grant you this statement looks to be true for mice - IF does not appear to provide the slowing of aging benefits provided by CR.

 

But given the uncertainty about whether CR benefits in rodents will translate to people [...] and given the fact that the primary markers we look for as indicators of 'successful' CR in people (reduced IGF-1, improved lipids, improved fasting glucose, reduced inflammation) also appear to result from IF (as this study illustrates), I don't see how the apparent certainty of your statement above ("...anywhere near..." & "...way off the mark") squares with the human evidence available.

 

Put another way, if we can't rule out that the benefits of CR for people may be largely a result of the health benefits of obesity avoidance, which you suggest in [1] as a reasonable way of interpreting the primate CR data in the section on "diminishing returns", and IF can accomplish the same, how can you be so certain of the inferiority of IF to CR in humans?

 

So, two things. First: the evidence that CR per se retards aging in rodents and many other species is very strong, but as you say, its human translatability is highly uncertain. Since the evidence shows that IF protocols don't even retard aging in mice, there's nothing to translate! If the fact that the robust effects of CR against aging in mice and multiple other species remain uncertain in humans makes the human practice a risky bet, it's at least a bet that is based on some positive evidence: here, the evidence is actually telling us that FMD nor IF (again, absent a substantial overall effect on energy intake) will not have such effects. I trust we're not going to react to the NIA CR study by adopting every putative anti-aging intervention that failed in mice!

 

Second, and relatedly: the human FMD biomaker data are interesting, but again: the only reason to pay attention to many of these markers in the first place is that they are potential signs of the translatability of CR to humans. In the case of IGF-1 in particular, there is reason to think that that the anti-aging effects of CR in rodents might be in part mediated by this reduction (though it's quite clear that that isn't the whole story). Since the FMD data don't show such benefits EVEN IN RODENTS, despite any reduction in IGF-1, there's no reason to get excited about n suggestions of translatability of its non-benefits.

 

Also, the magnitude of the effects are nowhere near as profound as those for CR proper, so if we're chasing after these effects on biomarkers, CR is the clear winner again. Indeed, if (as is a quite reasonable hupothesis) the reason why CR didn't work in the NIA study (or had only very weak effects) is just a dose-response effect, then again it's much less reasonable to expect a possible benefit from FMD than it is for CR.

 

In this study, in the rodents, "IGF-1 was reduced by ≈45% by the end of the FMD period but returned to normal levels, even after multiple FMD cycles (Figure S1F). IGFBP-1, which inhibits IGF-1, increased 8-fold by the end of the FMD regimen, but its concentration returned to levels similar to those for ad libitum mice within 1 week of re-feeding (Figure S1G)." Now, compare this to CR proper. In (1), 30%CR led to a durable 38% reduction in IGF-1 (from 315 to 194 ng/mL); in (2), somewhat surprisingly, 30%CR led to a 66% reduction (from 615 to 208).

 

In humans, "Circulating IGF-1 was reduced by ∼24% by the end of the FMD period (p < 0.001) and remained ∼15% lower after resuming the normal diet (p < 0.01; Figure 6D). IGFBP-1 was increased 1.5-fold at the end of the FMD regimen (p < 0.01) and returned to baseline levels following normal food intake ..."

 

So an FMD rodent spends most of its time with normal IGF-1 exposure, with bouts of profound reductions 4 days twice a month. Humans on FMD had never more than a 24% reduction, and for just 5 days every month, although somewhat surprisingly they did still have a 15% ongoing reduction for the rest of the month.

 

In humans, CR proper with RDAish protein intake led to what is presumably a steady 25% reduction in IGF-1.(4) And note an important compositional difference between the diets: I expect that most of the CR practitioners in (3) were omnivorous, even if they ate less animal protein than the average omivore, whereas the FMD fasting period was not only very low in protein in absolute terms (10% of 1090 Calories on day 1 of the semi-fast, and 9% of 725 Cal on days 2-5) but also completely non-animal. This is important, because we also know separately that consumption of vegetal proteins is much less IGF-1-inducing than animal proteins. This seems to have occurred in the vegans in (3), and corresponds with my very low levels of IGF-1 when on a slightly supra-RDA protein intake when that protein is overwhelmingly vegetal (and the disproportionately large effect of adding just a little dairy thereto), and Dean's ongoing low IGF-1 levels on a vegan diet in the face of not formally restricting and exhibiting weight gain consistent with healthy leanness rather than CR.

 

Before anyone starts freaking out abour the fact that the CR people in (3) "only" achieved a 25% reduction in IGF-1, (a) Paul McG's and my experience suggests that lower levels are achievable (though I have a hard time titrating the effect), and [b) the effects of CR on IGF-1 in rats are far less dramatic than they are in mice — yet CR still works. For instance, in (4), 30% CR in WT rats only lowered IGF-1 by 12.2% in youth (and the gap narrowed with age, as the CR animals' levels remained steady as the AL animals' declined to CR-like levels by 24-26 mo), and in (5), IGF-1 levels were 14-25% lower at each age group from 20% CR.

 

We don't, in the end, really know what the key mediators of CR's anti-aging effects are, and certainly IGF-1 is only part of the story. The rodent CR phenomenon justifies paying attention to IGF-1 in the first place as a sign of the translatability of the former — not the other way around.

 

Glucose and lipids: both weaker effects, and also consistent with the "metabolic disease" explanation given above. Again, if you have metabolic disease, there are more strongly evidence-based steps you can take; and if you undertake FMD, you may find a benefit for metabolic disease, but unlike for CR you will not have any evidence base for an additional and more profound effect on aging.

 

References

1: Al-Regaiey KA, Masternak MM, Bonkowski M, Sun L, Bartke A. Long-lived growth hormone receptor knockout mice: interaction of reduced insulin-like growth factor i/insulin signaling and caloric restriction. Endocrinology. 2005 Feb;146(2):851-60. Epub 2004 Oct 21. PubMed PMID: 15498882.

 

2: Moore T, Beltran L, Carbajal S, Strom S, Traag J, Hursting SD, DiGiovanni J. Dietary energy balance modulates signaling through the Akt/mammalian target of rapamycin pathways in multiple epithelial tissues. Cancer Prev Res (Phila). 2008 Jun;1(1):65-76. doi: 10.1158/1940-6207.CAPR-08-0022. Epub 2008 Mar 31. Erratum in: Cancer Prev Res (Phila Pa). 2009 Nov;2(11):999. PubMed PMID: 19138937.

 

3: Fontana L, Weiss EP, Villareal DT, Klein S, Holloszy JO. Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell. 2008 Oct;7(5):681-7. PubMed PMID: 18843793; PubMed Central PMCID: PMC2673798.

 

4: Zha Y, Taguchi T, Nazneen A, Shimokawa I, Higami Y, Razzaque MS. Genetic suppression of GH-IGF-1 activity, combined with lifelong caloric restriction, prevents age-related renal damage and prolongs the life span in rats. Am J Nephrol. 2008;28(5):755-64. doi: 10.1159/000128607. Epub 2008 Apr 24. PubMed PMID: 18434714.

 

5: Breese CR, Ingram RL, Sonntag WE. Influence of age and long-term dietary restriction on plasma insulin-like growth factor-1 (IGF-1), IGF-1 gene expression, and IGF-1 binding proteins. J Gerontol. 1991 Sep;46(5):B180-7. PubMed PMID: 1716275.

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Michael,

 

Thanks for the clarifications. It does seem like the benefits (e.g. reduced IGF-1, glucose and lipids) of Longo's intermittent fasting regime may be explained, at least in part, by the reduction in protein, especially animal protein, during the fasting periods.

 

We don't, in the end, really know what the key mediators of CR's anti-aging effects are, and certainly IGF-1 is only part of the story. The rodent CR phenomenon justifies paying attention to IGF-1 in the first place as a sign of the translatability of the former — not the other way around.

 

Agreed, but I would emphasize that IMO the best evidence we have for the translatability of CR from rodents to humans is Luigi Fontana's paper [1] comparing gene expression in rodents and humans (some of us!) subjected to CR. Its major finding was that:

 

...CR induces a significant down-regulation of the IGF-1/insulin/FOXO pathway both at the transcriptional and post-transcriptional level [in both mice and humans on CR - DP].

 

If intermittent fasting can induce similar changes to the IGF-1/insulin/FOXO pathway, as hinted at by Longo's work, it seems premature to rule out the potential that intermittent fasting could extend maximum lifespan, rather than just help people avoid metabolic diseases associated with aging. Just like the early failures of CR to extend lifespan due to mistakes in the protocol (e.g. too rapid onset), demonstrating true longevity benefits of intermittent fasting may simply be a matter of finding the right intermittent fasting protocol to keep from killing off the rodents early due to stress, nutrient deficiencies, etc.

 

(Albeit weak) support for this hypothesis comes from the fact that even with the clusters of deaths in the aged mice shortly after bouts of the 4-day fasts (suggesting stress-induced mortality), Longo still found that the longest-lived 25% of the fasted mice lived on average 7.6% longer than the control mice. In humans that would translate into about 6 extra years - which is nothing to sneeze at.

 

--Dean

 

[1] Mercken, Evi M., et al. "Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile." Aging cell 12.4 (2013): 645-651.

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Good stuff, and lucid arguments here. What appears clear to me is that we aren't going to solve the riddle of what, when, how, and why a particular diet is optimal for one individual's particular human longevity by continuing to study mice rather than people. Mice are not people. The mice model needs to become yesterday already. And we aren't going to study people because the science is just too stuck.

 

So soon it'll be time for Nadine (http://images.sciencedaily.com/2015/12/151229070713_1_540x360.jpg) to tell us what the hell to eat, don't eat, when, how much, and why. We need disruptive technologies entered into the CR and human longevity arenas. More words and more sad mice studies are just not good enough, imo.

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It is, of course, very difficult to get even what one might think to be very broad conclusions about "healthy" lifestyles for relatively broad swaths of the population from human studies; everything we think we know is crude, tentative, and decidedly not personal. Within that, we can get even more tentative information about what is better for an individual, but always based on some kind of surrogate outcome, as one doesn't have a an infinite supply of highly compliant identical twins to recruit into a clinical trial, for whom each of any number of variables could be tested in different single- and conbinatorial-variable controlled trials, nor the time machine to have them run all of these multi-decadal experiments before one is oneself born.

 

You can see what a hopeless mess came out of the nonhuman primate CR studies. We will not see better ones in our lifetimes, unless our lifetimes are long enough to make the experiments themselves moot — for us participating on the Forums today, and potentially for all of humanity. Even an urgent and successful run at it would be ten years in the organizing and financing, and another > 40 years in the running.

 

If you want to go beyond avoidance of specific diseases and premature incidence or accelerated progression of aging phenotypes and diseases, to test potential interventions in aging that might move the ball on one's "particular human longevity," you simply have to rely very substantially on cohorts of much shorter-lived model organisms. And for various reasons, the best model organisms available to us remain laboratory rodents. There's a reason why they're still the go-to critters for all biomedical research.

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^^ But those critter-abuse days ("...the best model organisms available to us remain laboratory rodents...") need to end. And they will end, I hope, and sooner rather than later with advancing technology. For example, if we look at human metabolism with our tens of trillions of cells performing their septillion interactions -- most of it completely mysterious -- we say shit man it's all way too complicated to untease. CR? We don't know if it works in humans, and if it works in mice we won't know if it's translatable. So the answer (in addition to SENS) must also include an intelligence greater than ours that is able to untease the complications of the human body and why we need less of some foods, more of others, none of this, one of that, blah blah.

 

What I'm saying is Watson should be finishing up Med school sometime soon, and so we'll finally start to see medicoprogress. Mice studies? Rhesus macaques? Twins? Nope. AI is what's needed -- more intelligence.

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What I'm saying is Watson should be finishing up Med school sometime soon, and so we'll finally start to see medicoprogress. Mice studies? Rhesus macaques? Twins? Nope. AI is what's needed -- more intelligence.

http://www.prweb.com/releases/2015/12/prweb13117207.htm

 

The Nutrino App Powered by Watson is now available for download from the Apple Store. The one-of-a-kind app for expectant mothers incorporates IBM's Watson technology into Nutrino's insights platform to give women real-time, personalized nutrition advice including meal recommendations and 24/7 nutritional support.

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