Incremental advances in understanding the genetics, epigenetics, and biochemistry of aging are gradually pushing the field forward.  In addition, there are occasional new ideas that have the potential for quantum advances that change the nature of the game.  Last week, there were two game-changers, originating from the US East and West coasts.

  1. Caloric Restriction has been the surest and best-documented way to add a few years to human life expectancy, with additional benefits for health and vitality along the way.  But few people have the discipline to stick with a restricted diet year after year, and in fact average BMI has been increasing for decades in America and Europe.  Valter Longo (U of S Calif) has been promoting the idea that intermittent fasting offers most of the benefits of CR, while demanding less discipline.  Last year, he documented impressive benefits from periodic fasting on water for 3 to 5 days.  Most people who try this practice compensate when the fast is over, and quickly gain back the weight that they lost; nevertheless the benefits persist.  This week, Longo offers us a 5 day diet that induces many of the same benefits as fasting, but need not disrupt anyone’s life, comfort, or energy level.
  2. The search for drugs that extend human life has been held back bureaucratically by the FDA’s  outdated idea of what a drug is for.  A drug can only be recognized or approved if it treats a disease, and aging is not a disease.  In fact, there are existing drugs that modestly slow aging (e.g., aspirin, melatonin) but they have been approved on a different basis, for different uses.  Nir Barzilai (Einstein College of Medicine) is a respected and well-established researcher who has thrown his reputation behind an initiative to change the FDA’s position.  He has designed a drug trial for metformin, the oldest and best treatment for Type 2 diabetes, to determine whether it can slow aging.  Of course, a great deal of pre-existing data suggests it will pass this test, and Barzilai will then propose that metformin be approved as a prescription for people not diagnosed with diabetes, as a preventive for cancer, diabetes, Alzheimer’s Disease, heart disease and stroke.

 

Allowing People to Eat While They’re Fasting

I got my start in aging science in 1996, after reading an article on Caloric Restriction by Richard Weindruch.  My first act as a researcher was to write a letter (USPS, not an email–this was 1996) to Weindruch and ask whether the timing or the kind of food mattered for life extension. “Not at all,” he answered, “calories are the bottom line.  Just make sure you get all necessary nutrients.”

Weindruch was well-informed, and what he said was state-of-the-art science in 1996, but today we know better.  Restricting protein and restricting particular nutrients have been shown to deliver some of the same benefits as a CR diet; and intermittent fasting has been validated as a life extension program in rodents, with strong evidence that it will work in people, too.  It’s a good thing, because sticking to a low-calorie diet is hard for most people.  Now Weindruch is approaching retirement and his compatriot Roy Walford left us in 2004.  Valter Longo  has picked up the mantle of practical CR research where they left off.

As I have come to expect, Longo does his homework.  The new publication is convincing because it combines theory and history with longevity studies in mice and yeast, and metabolic data from a new short-term trial in humans.

 

The Diet

The FMD (fasting-mimicking diet) is ketogenic, with restricted protein and a high percentage of calories from fat.  “Day 1 of the diet supplies 1,090 kcal (10% protein, 56% fat, 34% carbohydrate), days 2–5 are identical in formulation and provide 725 kcal (9% protein, 44% fat, 47% carbohydrate).”   The diet is predominantly fat.  The closest single food that approximates these macronutrient ratios is the avocado.  The diet approximates two avocados per day.  But you could construct the same macronutrient ratios using rice or apples and adding vegetable oil or small quantities of nuts.  I assume that green leafy vegetables could be added to the diet without changing its effect, while making it more palatable and filling and giving you a vehicle for the vegetable oil.

Here are three sample menus of my own construction (don’t blame Longo), each designed to give you ⅓ of the FMD nutrients for Day 1 or ½ the nutrients for Days 2-5. Each recipe has about 360 calories.  While these recipes mirror the macronutrient content of the FMD, they don’t have the same micronutrients, and they generally have a lot of extra leafy-green bulk (fiber).  My recipes haven’t been studied in a clinical trial.

[UPDATE added 8/1:  Link to list of recipes, created with data from USDA nutritional database, in cooperation with Enid Kassner.]

Sample Meal One:
4 oz salad greens + 4 oz cucumber
1 tbsp vegetable oil
1 tbsp vinegar
½ apple (~4 oz)
½ oz almonds

Sample Meal Two:
6 oz cauliflower
1.5 oz sesame tahini
1 oz lemon juice
4 oz blueberries

Sample Meal Three (red cabbage salad):
4 oz shredded red cabbage
3 oz shredded carrots
½ oz cilanthro
½ (mushed) avocado (~3 oz)
1 tbsp lime juice
2 tbsp apple juice
¾ oz walnuts
garlic and mustard to taste

Sample Meal Four (gazpacho):
12 oz canned or fresh tomatoes
4 oz fresh onion
1 tsp olive oil
4 oz black olives
2 tbsp vinegar
4 oz cucumber
3 oz snap peas
salt, black pepper, cayenne
(Blend together, leaving it chunky or smooth to taste)

Spice to taste–the effect on calories and macronutrients is negligible.  Salt freely and supplement with magnesium.

 

The Data, mice

Mice were put on the FMD for 4 days, twice per month, starting when they were already middle-aged (16 months for mice ~ 50 years for humans).  They lived 11% longer than control mice (median) though maximum life span was not increased.   There was some indication that the mice were unable to tolerate the FMD intervals when they were really old, that it was triggering their death, and the experimental protocol was modified so that FMD intervals were stopped when the mice were 29 months old (the human equivalent of 90 years).

Test mice fully compensated for the lost calories when they were returned to ad libitum feeding, but still they weighed less–same lean mass but less visceral fat.  FMD mice had improved cognitive performance, stronger immune systems, lower markers of inflammation, and lower fasting blood sugar.  When they died, it was less likely to be of lymphoma, which is what usually kills lab mice.

 

The Data, humans

Humans were on the FMD diet 5 days out of each month, in a preliminary test that ran for three months.  Like the rodents, humans compensated for the lost calories when they returned to free eating, but still lost weight (not lean mass, but body fat).

Blood sugar and markers of inflammation were down; fasting insulin and IGF-1 were lower.  The article made no mention of HDL or LDL cholesterol.  Longer term trials with more criteria for metabolic health are planned.

In case you can’t tell, I’m really impressed with Longo’s work.  I think he has advanced the practice of human nutrition in the last few years more than anything that has been done in decades.

 

Legitimizing Research in Anti-Aging Medicine

We already have, incidentally, a great deal of information about the benefits of metformin in people with Type 2 diabetes (T2D, or metabolic syndrome).  It has been the first-line drug for T2D for fifty years, and about 150 million people are taking metformin worldwide.  The huge numbers have made it easy to collect data on other diseases.  People taking metformin have lower rates of cancer, heart disease and dementia than people taking other diabetic drugs.  It is tempting to conclude that metformin forestalls the diseases of old age generally, but rates of all these diseases are already elevated in people with T2D.  The new question being asked is whether metformin will offer benefits for people who don’t have diabetes to begin with.  There is one Scottish study reporting that cancer rates for diabetics taking metformin are depressed below the rate for non-diabetics who don’t take metformin.  Now that’s promising.

Nature reported last week that FDA had scheduled a hearing on Wednesday past (6/24) to consider a proposed drug trial for metformin as an anti-aging remedy.  The protocol would be to identify patients who have symptoms of one of three age-related disease:  cardiovascular disease, cancer and dementia.  People with T2D would be excluded by design.  Subjects would be prescribed metformin or a placebo, and the researchers would look for an effect on the other two diseases.  This design is a clever compromise between bureaucratic requirements and clean experimental methodology.  The bureaucratic requirement is that people assigned to take the drug must already be diagnosed with a recognized disease.  But it is the potential of metformin to reduce risk of the diseases that the subjects do not have that is the target question for the study.

Barzilai already has a small, ongoing trial for metformin and aging registered at ClinicalTrials.gov.  Just 15 patients will be enrolled, and the plan is to look at their gene expression profiles to see if metformin has an anti-aging effect.  A growing number of researchers (including me) thinks that gene expression drives aging, and last year, Steve Horvath of UCLA published a protocol for measuring physical age of the human body by combining epigenetic markers (methylation) from hundreds of different chromosome sites that empirically appear most sensitive to age.  They use the acronym MILES for Metformin In Longevity Study.

The new study is far more ambitious.

Plans call for the trial to enrol 3,000 people aged 70–80 years at roughly 15 centres around the United States. The trial will take 5–7 years and cost US$50 million, Barzilai estimates, although it does not yet have funding.

That’s $17,000 per patient, for a drug that costs pennies.  Certainly the cost will hold up this project, and monitoring patients for diseases that are already covered in their annual physicals.  Why does it need to be so expensive?

I have written to Barzilai about the Wednesday meeting with FDA and he would only say to watch for an article in next week’s Science magazine.

 

In the Larger Scheme…

The shortcut to modest gains in longevity is to work with the body’s adaptation to caloric restriction.  CR is known to work in many different animals, and is known to offer health benefits in humans, (although human longevity studies are probably completely impractical).  So the search is on for “CR mimetics”, drugs that will put the body into a calorie-deprived state without actually having to eat less.  Intermittent fasting, the Longo diet, and metformin all work on the same pathway as CR.  Some researchers believe resveratrol works on this same pathway, and even for rapamycin there is significant overlap with the CR mechanism.

It is understandable that researchers should be investing their time and pharmaceutical companies their money in this area, because this is where returns on investment are surest.  But the potential of this approach is limited to a few years of life extension, and layering metformin on CR on fasting on resveratrol on rapamycin will not add more years, just the same few years many times over.  As I have said in previous columns, there is immediate potential in telomerase activation, and longer term my highest priority would be to understand the epigenetic changes that come with age.