Metabolic Flexibility

Humans evolved in the setting of periodic food scarcity during which we developed the ability to rapidly switch between different fuel sources.  We are designed by evolution to burn fat in our fasting state and to burn primarily carbohydrates in our fed state in order to generate energy in the form of ATP.  All of this occurs in our mitochondria.  But with the development of the modern industrial food environment and ready access to overnutrition combined with less energy expenditure compared to the conditions under which we evolved, we find ourselves overnourished and at odds with our evolutionary design.  One consequence of this mismatch is impaired fuel switching in the mitochondria—we lose the ability to easily switch between lipids and glucose that marks a healthy metabolism.  As a result, our engines are inefficient, we have trouble burning fat while fasting, we are hungrier sooner after a meal, we eat more and find ourselves in a feed forward loop.  Eventually we develop obesity and the diseases related to insulin resistance such as diabetes, metabolic syndrome, NAFLD and ultimately cancer.   At least these are the claims.  What follows is an abstract of a good review paper published earlier this week that examines the concept of metabolic flexibility.

How and why does metabolic inflexibility occur?  

With chronic overnutrition (aka the Standard American Diet), cells become overstuffed and congested with macronutrients, overwhelming the enzymatic mechanisms of metabolism and leading to accumulation of incompletely oxidized substrates–the details of this process are probably not as interesting for our purposes as are the consequences.  These substrates harm mitochondria through oxidative stress from free radical damage and acetylation / protein modification due to acetyl coA accumulation.  The damage actually reduces the number of mitochondria as well as changing their functional morphology–the mitochondria look different and their performance is degraded.   The plasticity of the fuel switch deteriorates, leading to a sluggish metabolic response to nutritional cues.  Imagine a hybrid vehicle whose gas motor is flooded and so it can only use electricity.  And maybe the gas tank is expansile and is ever filling.  I wish I could think of a better metaphor but I’m a poor mechanic.

At the same time, the overfed state also requires increasing amounts of insulin to push glucose into cells via insulin dependent glut4 transporters.  Imagine insulin to be the hose pressure pushing gas into the tank.  The more stuffed the cells are, the more insulin you need to drive nutrition intracellularly, and this is precisely the phenotype of insulin resistance.  Glucose that should be going into the muscles and fat cells is taken up by the liver and converted to fat through de novo lipogenesis, leading to NAFLD–now the leading cause of liver failure.  The very high circulating levels of insulin cause sodium retention in the kidney creating salt-sensitive hypertension.  Insulin is also a growth factor, and high levels are associated with carcinogenesis.  Finally, the pancreas burns out, can no longer make insulin and we develop type 2 diabetes. This is the backstory of the American healthcare system.

Insulin resistance and metabolic inflexibility are intertwined and it’s not clear which comes first, but they relate to each other and are both a consequence of overfeeding.  One reason this topic is of clinical interest is that people with metabolic inflexibility have problems burning fat in the fasting state.  They get hungry sooner and have trouble with fasting.

How do we treat this metabolic rigidity?

  1. Diminish the nutrition going into the cell
    1. Caloric restriction: since the problem begins with too much energy, an energy deficit, regardless of macronutrient balance, is a reasonable first step toward relieving substrate competition.  I don’t think you need to go low carb or keto, though some people may find it easier to do so in order to manage their hunger.  Calorie restriction permits cells to decongest themselves of unused substrate and restore normal membrane potential across mitochondria.  Losing weight is the best and perhaps only valid treatment for fatty liver and can reverse insulin resistance and DM2 in its early stages.  So eating less is how to repair the metabolic inflexibility which derives from eating too much–it feels like an astute observation of the obvious, but there may be a special way of eating less that is especially effective.  Fasting.
    2. Fasting: starvation has benefits beyond calorie restriction alone.  We evolved to cope with periods of starvation and the metabolic program triggered by fasting has diverse benefits beginning with exhaustion of liver glycogen stores and initiation of ketosis. Burning ketones is metabolically healthy for a number of reasons, particularly as we age.  At the cellular level, fasting induces autophagy to remove damaged proteins, mitochondrial biogenesis and mitophagy.  The issue of fasting is, of course, a larger one and care must be taken to preserve lean muscle mass, but the rationale to starting a diet with a fast is that lipid oxidation is kickstarted by more rapidly inducing metabolic flexibility.
    3. SGLT2 inhibitors:  SGLT2 (sodium glucose cotransporter-2) inhibitors force the kidneys to spill glucose in the urine leading to a condition that mimics caloric restriction.  These drugs have been shown to be kidney protective, to reduce weight, to reduce blood pressure and to improve outcomes in congestive heart failure.  It turns out that they also promote beiging of adipocytes (in mice)—the brown fat that generates heat and burns calories in the process.  Unclear if this is relevant in humans.  At the mitochondrial level, SGLT2i’s permit the cell to decongest itself of the metabolic substrates that have caused all the damage.  Taking SGLT2i at night, according to the authors, amplifies the effects of an overnight fast.
  1. Improve factors that mitigate mitochondrial stress
    1. Restoration of glutathione with glyNAC to counter oxidant stress
    2. Carnitine based acetyl-group buffering: theoretical. I don’t see any evidence that carnitine supplementation is of value at this point.
  1. Increase energy expenditure
    1. Aerobic exercise, particularly zone 2 exercise is a best way to improve the number of mitochondria and their function. There is a strong association described between exercise and metabolic flexibility.  Even after one episode of exercise, insulin resistance and mitochondrial function improve.
    2. Resistance training: bigger muscles means a bigger glucose sink, a greater buffer to accommodate nutrient load in the fed state.



Autophagy (literally “self-eating”) is the body’s way of cleansing cells by recycling old or damaged components and is a process that appears to have a strong relationship to preventing disease and aging.  More technically, it is a highly regulated lysosome-dependent catabolic program used by the body to clear dysfunctional proteins, organelles and other structures that are typically first marked for the process by a protein called “ubiquitin.”  Primarily intra-cellular but also extra-cellular components are engulfed in autophagocytic vacuoles and degraded to constituent molecules, such as sugars, fatty acids and amino acids, which can be then be used as nutrition to produce ATP and/or provide building blocks for the synthesis of essential proteins.   There are different types of autophagy but for the most part they all serve this same purpose.  Mitophagy is a similar process that removes damaged or dysfunctional mitochondria.  There is also nucleophagy of material in the cell nucleus.


A number of types of autophagy are currently described.

  • Microautophagy: direct engulfment of cytoplasmic materials by invagination of lysosomal membrane.
  • Macroautophagy:  classic autophagasome mediated double membrane engulfment.
  • Chaperone Mediated autophagy: extremely selective target protein mediated (Hsc70) recycling that is activated in response to cellular stress.
  • Mitophagy:  autophagy related to mitochondria and their components
  • Also… ribophagy, lipophagy, xenophyagy, nucleophagy, clockophagy, lysophagy, etc.


Why is it important?
Autophagy is critical to cell function, regeneration and keeping the cell working properly.  Inhibition of autophagy by knocking out any of a variety of autophagy related genes invariably accelerates aging and disease.  Similarly, with aging, autophagy is downregulated (particularly in lymphocytes) leading to a forward feeding loop of accumulation of cellular debris and cellular dysfunction / dysregulation.   In contrast, enhanced autophagy delays aging and prolongs lifespan in a range of model organisms including yeast, nematodes, fruit flies and mice.  Lifespan studies in humans have not been conducted given the obvious challenges in conducting experiments in long-lived organisms, but it is generally assumed that regular induction of autophagy is a salubrious process, something we want to promote.  So how to do so?

How to promote autophagy?
First the biochemistry–skip ahead to the punchline if you prefer.  ULK1 is the enzyme that catalyzes production of phagosomes implicated in autophagy.  AMPK and SIRT activate ULK1, MTOR deactivates it.  If MTOR1 is inhibited by rapaymycin or starvation, autophagy is activated.  TFEB is considered the primary transcription factor for the synthesis of both lysosome and autophagosomes.   Again, AMPK boosts the activity of TFEB while MTOR inhibits it.  Spermidine, which declines with age, is a required co-factor in the translation of TFEB, so its supplementation is theorized (and shown) to stimulate autophagy.

Caloric restriction activates autophagy by stimulating AMPK and sirtuin1 as well as inhibiting mTOR.  When an autophagy related gene is knocked out or knocked down, the life-prolonging effect of rapamycin disappears, suggesting that autophagy plays an important role in the life-prolonging effect of rapamycin.

Simply not eating for a few hours and reducing nutrient levels in the blood starts the process of autophagy.  This is the rationale for time restricted feeding.  Starvation for longer periods such as two- or three-days initiates chaperone mediated autophagy, a targeted deep clean that modulates diverse functions such as glucose and lipid metabolism, DNA repair, cellular reprograming and the cellular response to stress.

Drugs to stimulate autophagy

  • Berberine and metformin both boost AMPK, thus phosphorylating and activating ULK1–> autophagy.
  • Rapamycin and spermidine inhibit MTOR, activating autophagy and spermidine, as already mentioned, both blocks motor and also is a necessary cofactor in the translation of TFEB.
  • Resveratrol and NR (nicotinamide riboside) theoretically target SIRT1, though evidence of their bioavailability after oral administration is questionable.
  • Ferulic acid may up-regulate SIRT1 expression and is derived from Angelica sinensis or “female ginseng” and used in traditional Chinese medicine.  It is also widely available as an additive in cosmetic skin creams.  Anthrocyanins in the diet are converted to ferric acid, providing a rationale for their health value.
  • Urolithin-A, a phytochemical derived from pomegranate has also been shown to boost SIRT1, as well as improve mitochondrial biogenesis.
  • Aerobic exercise has also been shown to stimulate autophagy.
  • It turns out these are all the usual suspects in the realm of anti-aging drugs and supplements, and while many of them have diverse actions, it may be that their action on the autophagy pathways is primary to their purported value as anti-aging interventions.  Yet the effect sizes of these interventions are not known, which is to say that we don’t really know to what extent autophagy will be triggered by taking any of these.

Can there be too much autophagy?  Perhaps yes.  While normal or even supernormal levels of autophagy promote cellular health, excessive or uncontrolled autophagy can initiate a type of cell death known as “autosis” (  While autophagy is believed to be helpful, cell death through autosis is inarguably harmful and to be avoided.  The clinical significance of autosis in the context of therapeutic autophagy is not clear.  I reached out to Beth Levine, the woman who did much of the original research on autosis but her email bounced back and it turns out she has tragically died of breast cancer.  In any case, in this setting of incomplete understanding, the best course is one of prudence and moderation.  In the words of Hippocrates, first do no harm.  Practically speaking, my policy is to cycle agents, to avoid excessive dosing and to carefully follow serologic markers during treatment.

Relationship between autophagy and weight?
There is an emerging understanding of a relationship between autophagy in the medial-basal-hypothalamus (MBH) and obesity mediated by the FK506 (tacrolimus) binding protein FKBP51, which appears to be a major upstream regulator of autophagy.  Could autophagy and more broadly, the intracellular environment in hypothalamic neurons be the functional memory that induces phenomena such as the physiologic set point?  Could agents that augment autophagy such as rapamycin reset the physiologic set point in humans, as it has in mouse models?  These are intriguing questions.

Epigenetic clocks and Reprogramming  

How do we measure aging?  Certainly, there is the passage of time and how many birthdays someone has had, but we know that aging proceeds more quickly for some people than it does for others.  The speed of aging depends on your genes but also various factors such as, for instance, whether you smoke, your diet and level of exercise, your stress levels, exposure to ionizing radiation, and many other variables.  A 50 year old executive will likely be biologically younger than a 50 year old homeless alcoholic who has had a hard life, to take an example.  Is there some other marker that indicates a biological age that is distinct from chronological age?  This question is critically important if we are to assess the effectiveness of anti-aging interventions and has been a matter of much debate.  Recently as our understanding of aging has evolved, scientists have focused on methylation patterns in the DNA as a likely proxy for aging.

These so-called methylation clocks presuppose a process of epigenetic aging in which the organism’s DNA is gradually ornamented with methyl groups and that this methylation pattern is a good indicator of how old someone really is.  These methylations happen at points in the genome where cytosine is bound to guanine through a phosphate group (CpG).  When these CpG sites are methylated, it changes the three-dimensional structure of the DNA and changes the way that DNA can be expressed.  The theory holds that the loss of function with aging happens because the heavily methylated DNA is shaped differently and cannot be read (or transcribed) as easily as it once was.

These methylation patterns were discovered using deep computer learning analysis of tissue samples, by Steve Horvath and others made possible by affordable array-based technologies and massive amounts of publicly available human methylation data.  Horvath was able to identify 353 CpG methylation sites that predicted the progression of aging from embryonic stem cell to old age.   Of note, this is a very small fraction of the total number of CpG sites, which is itself a small fraction of the other methylations, histone acetylations and other changes that happen with age, so keep in mind that this is a highly focused view on a a process that is immensely more widespread.  Since his pioneering work, many different age clocks have been described which employ a variety of clusters of CpG methylation sites.  It’s not clear if these clocks are measuring the same thing[i].  In fact, the different clocks may be measuring different biological processes.  And this makes sense, since we know that aging proceeds at different rates across different physiologic systems, it’s not going to be a question of a particular clock as it is of multiple clocks, ticking independently.  How do you assess aging in different tissues like the brain?  At this point, genetic material is not sampled from each tissue—nobody is doing brain biopsies— but rather only from white blood cells, and then methylation sites are assigned to tissues based on the type of protein coded by the DNA region.

Are these methylation patterns a marker for aging or are they actually driving aging?  This is not a settled question.  We do know that increased epigenetic age relative to chronological age has been linked to disease and mortality risk.  And removing methylations in mouse retinal cells (using Yamanake factors, see below) and reintroducing these cells into the retina using a viral vector reversed vision loss and cured blindness in mice.[ii]   The researchers believed that they were reprogramming the cells to an earlier (younger) state of their progression on the program of methylation.   Reprogramming means taking aged or otherwise faulty cells and tissue that have already grown and “differentiated,” and resetting them closer to an original state of induced pluripotency.  This is done using a group of transcription factors called Yamanake factors, discovered by the Nobel laureate Shinya Yamanaka.  These Yamanake transcription factors regulate the expression of DNA in such a way that the cell returns to a state where it can become any kind of tissue.  They are:

Oct-3/4:  transcription factors critical for maintaining pluripotency and preventing cell differentiation
Sox family:  important for sex determination but also maintenance of pluripotency
KLF4: regulation of apopotosis, tumor suppression
c-Myc: proto-oncogene

One of the actions of the Yamanke factors is to make possible the de-methylation of the same CpG groups that are theorized to drive differentiation and aging.  Myc is sometimes left out because it is associated with uncontrolled growth, leaving Oct/Sox/KLF aka “OSK” treatment.  OSK treatment in mice has been shown to reduce levels of methylation and also to restore function.  If reprogramming with OSK is pursued to its natural conclusion, cells return to pluripotency and can become cancerous.  However, if the reprogramming is done incompletely, then the cell simply becomes younger.  This is the aim of cellular reprogramming in a nutshell, and an enormous amount of money is being invested in this field ($3 billion for Bezos funded Altos labs last week) to capitalize on the technology.  The goal will be to safely do partial reprogramming, to avoid pluripotency and the risk for malignancy.  In a recent paper, they appear to have done just that with mice.

What is driving the methylations?  Is it just DNA damage, a stochastic and random process, as David Sinclair has proposed?  Or is it some programmatic process from birth to death?   We don’t know yet.  One observation supporting randomness is that methylation changes are more likely to occur at early and late replication sites in DNA.  In other words, when a cell divides and DNA is copied to create two daughter cells, the epigenetic changes are also copied.  The observation that the epigenetic changes are concentrated at specific sites relevant to the replication process suggests some mechanical issue rather than an external program driving methylation from embryogenesis to old age.  On the other hand, how is would it be that all cells in the body (or at least a statistical majority) should change their epigenomic methylation patterns simultaneously?  The improbability of this occurrence argues for a central regulator.  Thus far, empiric evidence either way is scant.

Another question is whether reprogramming creates a truly rejuvenated cell in every sense of the word.  We know treatment with Yamanake does not remove all methylations, but only important subsets of them. Is there longevity for these cells?  How do they behave over time.  These are questions that remain to be resolved.  Hopefully in the next decade we will see clinical applications that derive from this technology in human beings.  It will be expensive at first, but I’m sure at least one child with a previously incurable disease will be granted a normal life thanks to reprogramming.  And he or she will be free to age normally and watch the world gradually warm to uninhabitable levels and descend into geopolitical chaos, but that is a matter for another blog post.



Weight Set Point Theory

The real challenge with weight loss is keeping the weight off. 

When you lose a significant amount of weight (greater than 10% is the number that’s typically used, though certainly there is individual variability), the body does what it can to return to its original weight, leading to the much-heralded phenomenon of yo-yo dieting.  The body seems to have a weight set point that it defends despite the extent of its internal stores of energy (in the form of fat).   The set point can increase over time because of environmental and physiological reasons.  For example the hormonal changes of pregnancy or significant prolonged cortisol release from stress.  Alternatively being placed in a new food environment such as going to college or working from home during a pandemic.  These changes can raise a person’s set point, but lowering it is a harder job.  Regardless of where the set point resides, when we lose weight below the set point, the body counters with metabolic adaptive physiological processes that evolved to defend itself from starvation. These include the following mechanisms.

  1. Thyroid function changes.  Reverse T3 increases, T3 and T4 decrease, effectively rendering you hypothyroid
  2. Muscle efficiency increases (improved muscle function per calorie, less wasted calories)
  3. Neuro-humoral changes:  leptin, CCK, peptide YY all DECREASE, thus removing inhibitory actions on ghrelin, increasing appetite
  4. Decrease in resting energy expenditure due to weight loss and less available metabolically active tissue
  5. Adaptive thermogenesis decreases resulting in reduced resting metabolic rate
  6. Decreased sympathetic tone, increased parasympathetic tone
  7. Commitment amnesia:  relapse of maintenance behavior that were required to lose the initial weight

As a result, fewer than one out of six people who have lost a significant amount of weight can keep it off after a year. Even more alarmingly, there is a concern that by weight cycling, you end up resetting your basal metabolic rate lower across all weights.  So even after you regain the weight, you are still burning less calories, even at rest.  Why might this happen?

With weight regain, the body’s imperative can be understood as follows:  it wants to reconstitute fat free mass (FFM).  This includes lean muscle but also the weight of organs, bones and other non-fatty tissues in the body.   In Keys’ famous Minnesota weight loss experiment with conscientious objectors to WW2, over-eating and weight gain did not abate until FFM was reconstituted.  During weight regain, there was a desynchronization in the reconstitution of fat mass and fat free mass, so subjects ended up with an overshoot of fat return.  Meaning when you regain the weight, you end up with an increased percentage of fat as compared to muscle.  Fat is a less metabolically active tissue and so you should theoretically have a lower BMR at the new weight, and this is what is observed.

Is there a solution?  Possibly, and we’ll get to that.

Where does the set point reside?

How is this set point encoded and where does it reside in the body?  We don’t really know for sure but allost certainly in the subcortical regions of the brain.  More specifically the hypothalamus.  Possibly more specifically, in the arcuate nucleus of the hypothalamus, where the major nuclei relevant to maintenance of weight reside.  One theory is that specific neuronal cells called astrocytes in the arcuate nucleus either sense changes in nutrition or somehow are attuned to loss of weight, possibly in relation to lepton levels.  As a result they are activated in a process known as reactive gliosis.[i]  Other epigenetic changes are encoded in various parts of the brain and body as a consequence of weight loss leading to the defended phenotype.  The symptoms of this condition are excess hunger and reduced satiety as compared to normal people.  Nobody knows exactly what the thermostat is measuring.  It could be circulating fat or lepton, it could be some factor related to fat free mass.

Bariatric surgery seems to evade some of the post-weight loss changes related to a set point, but why this happens is not completely understood.  The commonly performed surgeries change the composition and concentration of bile-acids, which are important signals of satiety.  Also, because of structural changes in the gut, more nutrition passes to the distal part of the intestine causing increases in anorexigenic hormones such as GLP1 and PYY (hindgut hypothesis).  There may also be changes in direct signaling to the CNS.  Then the mechanical issues: the stomach is smaller, there is a fear of dumping syndrome if you eat too fast, etc.  All of these factors contribute to a functional reduction in set point.  But bariatric surgery is not the only way to lower the set point.

But then how do we keep the weight off?

One basic principle is that if you must lose large amounts of weight, then do it slowly so that the body gradually adjusts to a lower set point.    Losing weight more deliberately and pausing between plateaus seems to help people evade the set point phenomenon and thus maintain reduced body weight,[ii] though to be clear, this finding is anecdotal and lacks experimental proof.

Beyond that, attention needs to be paid to muscle.  When you lose weight, you lose both fat and fat free mass.  Fat free mass includes the weight of organs and other tissues, but also muscle.  When you regain the weight in the context of increased muscle mass, you will regain fewer pounds of fat.  In other words, muscle mass will protect against fat regain.  There are medications that should be used to mitigate the set point or even reset it. Ultimately, weight loss needs to be done in a controlled fashion with a plan, with frequent pauses to permit the body to catch up.  Muscle mass facilitates this process.

Dietary characteristics are also important.  I suggest a diet that is somewhat less palatable, with less sugar, salt, fat and calorie density, more fiber.  The diet will be satiating but less rewarding.  If you can stick to a diet like this for a few weeks, it will change the way your brain defends its adiposity.

Finally no discussion of weight is complete without a mention of exercise, sleep and stress management.  While these may not be critical in weight loss, they are important in resetting the ponderostat, or body weight set point.




Drugs For Obesity

Sometimes no matter how hard we exercise or how conscientiously we diet, the weight does not come off.   A short fast can jump start the process of fat oxidation, but we are also fortunate to have FDA-approved drugs to help us along if we cannot get started. Or if we plateau.   We offer medications when BMI reaches 30 (or over 27 with complications related to obesity).  Even before drugs, though, the first step is to make sure you’re not taking other prescription medications that cause weight gain.  Some of the bad actors in this realm include sulfonylureas for diabetes, certain antidepressants and antipsychotics, carbamazepine and valproate, beta-blockers and some other medications.

And before we launch on a discussion of medications, let me suggest that obesity should never be treated with just medications.  You need to establish healthy and enduring habits of nutrition and activity, otherwise the weight will just reaccumulate when you stop taking the pill.  I don’t consider a lifetime of drug therapy to be a success.

What follows is a list of the FDA-approved therapies along with my thoughts about each.  Ultimately, the decision to start medication and which one to choose is one you should make with your doctor, and it depends on each drug’s advantages and disadvantages as well as your own medical history and physiology.

    1. PHENTERAMINE:  is a stimulant, a schedule IV controlled substance, and so I’m naturally biased against it, and though there’s evidence that it is not habit-forming1, it can raise blood pressure.  It works because it reduces appetite but may be associated with anxiety, insomnia, and palpitations.  One plus is that phentermine is relatively inexpensive.  Nevertheless, there are better drugs available and I prefer not to prescribe it.  In some health systems, insurance companies require patients to fail a trial of phentermine before they will cover other more expensive drugs.
    2. PHENTERMINE / TOPIIMATE ER (QSYMIA): here we add topiramate, an anti-seizure drug with appetite suppressive properties to phentermine.  The combination is more effective than either alone and you can expect to lose about 10% of body weight after a year.   Maybe I’m less set against this one because the phentermine dose does not get as high, nevertheless, I’ve never prescribed it.
    3. ORLISTAT: here’s one that’s fairly safe, it inhibits the absorption of dietary fat, so this is a good adjunct to a low carb diet.  You can buy it in a lower dose without a prescription on Amazon, so what’s not to love?  Well, urgent, explosive, greasy stools, for one.  When you inhibit the metabolism of lipids, the fat passes through your system and changes your bathroom experience.  But if you have chronic constipation, then this might be a serendipitous plus. A second consideration is that it takes your fat-soluble vitamins with it (A,D,E,K), so you really need to supplement with a multivitamin if you’re going to take this medicine.  Most patients do not like this drug.
    4. NALTREXONE / BUPROPION (CONTRAVE): this is a fascinating drug that works by reducing hunger cravings in the brain.  Let us nerd out on the mechanism for a moment.  Bupropion is an anti-depressant that has the unexpected effect of stimulating the cleavage of a large molecule called POMC.  One of the cleavage products is a-MSH, which activates the melanocortin-4-receptor (MC4R), which reduces appetite and increases energy expenditure.  Another cleavage product of POMC, beta-endorphin, feeds-back to inhibit cleavage of POMC.  But that’s where naltrexone comes in, it blocks the inhibition of POMC cleavage, resulting in unopposed stimulation of MC4R.  Beware though that naltrexone blocks the action of opiates more broadly, so if you take opiate pain medication, this drug is definitely not for you. However, Contrave does seem to have a role in attenuating addictive pathways in the brain, so it might be an appropriate choice for someone who wants to cut down on smoking and/or drinking.
    5. GLP1 RECEPTOR AGONISTS (LIRAGUTIDE, SEMAGLUTIDE): these drugs are now both FDA approved for weight loss and they work very well.  Semaglutide has gotten a lot of press as a “game-changer” and it may actually be one—it’s a once-a-week drug that has been associated with loss of up to 20% of body weight.  The drugs imitate the effect of a molecule called GLP-1, which has a range of effects including delaying emptying of the stomach, reducing appetite, and increasing the secretion of insulin.  One would think that increased insulin is bad, but in one meta-analysis, GLP-1RA’s were associated with fewer strokes, fewer cardiovascular events, and lower all-cause mortality in a diabetic population.2  Not clear yet if this holds for non-diabetics as well, but needless to say, it makes this a very appealing medicine.  In mice, a recent article suggests GLP1RA’s reduce brain aging.3  What are the negatives?  First, the cost.  They’re expensive, but if your insurance covers them, you’re lucky.  If not, there are some other tricks to getting it at lower cost.  Second, semaglutide, while once a week, is delivered as an injection–which is a bridge too far for some.  Finally, even though the official account is that these drugs are not associated with pancreatitis, I’ve had one patient on semaglutide develop a severe case, so that experience sits in the back of my mind.  Nevertheless, these seem to be a class of agents that represent a great leap forward and a great option for people who can afford them. In all likelihood, liraglutide will go the way of the Betamax because you have to take it every day and semaglutide will be a widely prescribed drug.

Beyond these drugs that are FDA approved to treat obesity, there are metformin, SGLT2 inhibitors, and others that will afford you some weight loss and metabolic benefit and may occasionally be appropriate.  Canagliflozin, an SGLT2 inhibitor, has shown promise in the interventions testing protocol conducted by Richard Miller at the National Institute of Health as a longevity drug.  Metformin is also a promising drug for non-diabetics and is being investigated for its purported life-extension properties by Dr. Nir Barzelai.

1 (Hendricks, E. J., et al. “Addiction potential of phentermine prescribed during long-term treatment of obesity.” International journal of obesity 38.2 (2014): 292-298.)
2 Malhotra, Konark, et al. “GLP-1 receptor agonists in diabetes for stroke prevention: a systematic review and meta-analysis.” Journal of neurology 267.7 (2020): 2117-2122.
3Li, Zhongqi, et al. “Systemic GLP-1R agonist treatment reverses mouse glial and neurovascular cell transcriptomic aging signatures in a genome-wide manner.” Communications biology 4.1 (2021): 1-6.