MYC: Bad and Good, but More Bad than Good

MYC is the name of a gene that promotes cancer.  We’ve known this since the 1970s.  Trouble is, MYC is also necessary for growth, so we can’t eliminate it, and we’ve been very careful about targeting targeting MYC for inhibition, except in the extreme case of cancer patients.  That’s why we didn’t learn until last week that mice with half as much MYC live longer and seem healthier in every way.

The standard theory of why we age is called “Antagonistic Pleiotropy”, a fancy way of saying that nature has been forced to compromise.  Natural selection rewards long life, it is true, but also rewards rapid growth and high fertility.  It is genes like MYC that force nature into a kind of devil’s bargain, accepting a cancer risk (and a shorter life) as a necessary concomitant of growth and fertility.

This idea was a gift of George Williams [1957], last week’s featured celeb here at Aging Matters, and for more than 50 years it has been so well-established that scientists presume–not just evolutionary scientists, but also clinicians and medical researchers presume that nature has done her best by us, and we oughtn’t to tamper with the mix of genes that Nature has bequeathed us.

Inserting or deleting a gene has become so routine in thousands of research labs around the world that it is only surprising it has taken so long before researchers at Brown University prepared mice with one parental copy of the MYC gene missing, and the second intact.  Last week they reported that the mice lived longer, were less susceptible to cancer, were more active, had healthier blood lipid profiles, and their immune function remained stronger, longer.  Heart muscles stayed more pliable, and cholesterol buildups occurred later.  The mice died of the same cancers as normal lab mice, but later.  (Mice missing both copies of MYC are not viable.)

Most interventions that extend life span in mice work by dialing up the stress response system.  This is the mechanism of hormesis, a beneficial over-compensation to stress.  Caloric restriction is the most common and most consistent way to activate this pathway.  So it is interesting to note that the mice with reduced MYC did not have increased stress response, nor did they eat less than normal mice.  This suggests that the life extension benefit of reduced MYC might be able to synergize with caloric restriction to offer additive benefit.

Many anti-aging measures have tradeoffs. Mice given rapamycin, for instance, have increased cardiovascular disease risk and reduced immune function. In contrast, mice with reduced MYC showed no obvious health problems and were able to reproduce normally. [ref]

Life span was extended 20% for females, 10% for males.  This, too, is unusual, in that, where there is a difference, other interventions commonly extend male life span more readily than female.

MYC is a “transcription factor”, which means it acts by turning other genes on and off.  In fact, MYC is one of the most powerful, broad-action transcription factors, with effects on the activities of thousands of other genes.  One hint about the mechanism of action is that reduced MYC leads to less active ribosomes, the organelles in which proteins are transcribed.  MYC+/- animals have less of every kind of protein, and it is no longer surprising that this leads to extended life span.

MYC has been identified in the past as an intermediary that is necessary to help turn on telomerase activity in response to caloric restriction and mimetics (drugs that act like CR).  The Brown team was encouraged to report that mice with half their MYC missing did not lack for telomerase.

 

What can be done for people who are unfortunate to have been born already with two copies of the MYC gene?

That MYC is overexpressed in cancer cells has been known a long time.  Much of the work on MYC and how to turn it off has been done in the course of a search for effective  cancer treatments.  Peter Vogt’s lab at Scripps Inst in La Jolla has led this charge.  They have searched through thousands of small molecules, looking for chemicals that “turn off” MYC or interfere with its actions.  Here is a paper that catalogs dozens of small molecules that have been studied for their ability to either stop MYC from being transcribed or inhibit the MYC protein from acting.  I was amused to note that the standard notion of a “small” molecule extends to include a great deal of complexity.  The standard for “small” is scaled by protein macromolecules that are fold from thousands of chained amino acids.

MYC-inhibitors

But the abundance of candidate molecules isn’t necessarily good news.  It means that researchers have followed a well-worn path and pursued many candidate drugs, all with limited success for one reason or another.

It is rare to discover death genes, pure and simple–genes that have no other purpose than to kill us.  Such genes are known (or suspected) in worms [ref] but not humans.  But the list of genes that have been co-opted for programmed death is substantial.  I have reported some here last year: TOR, NFk-B, IGF-1, wnt etc.  These genes are over-expressed, especially in old age, with consequences that are purely detrimental.  They make attractive targets for anti-aging therapy.

In other words, death on a schedule is programmed into our genes, but not with specific “time bomb” genes.  Rather, the program works by co-opting genes that have other uses early in life, but that are deployed for the purpose of self-destruction late in life. The classic example is inflammation, which is an important mechanism of defense, but which is loosed upon healthy cells, causing cancer and dementia late in life.

So MYC is one of those genes without which we can’t live and grow, but late in life it slips its leash and causes great damage.  It might serve us well to keep MYC under tighter control, if we can find a practical means to do so.

 


 

I am grateful for this and many ideas to Reason over at FightAging! web site and newsletter.  Week after week, he does a superb job of collecting and summarizing news and research in the field of anti-aging medicine. His viewpoint is a bit more mainstream than my own.* Readers of this page may be interested in subscribing.

In addition to MYC, this week’s newsletter also includes

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* Where he sees damage that the body suffers despite its best efforts to resist, I see epigenetically progammed self-destruction.

 

4 thoughts on “MYC: Bad and Good, but More Bad than Good

  1. So I don’t believe in ‘antagonistic pleiotropy’ I think you’ve hit the nail on the head though in noting that it is neither the presence or absence of MYC (as most ‘wear and tearers’ think), but the amount of the gene that is the problem. It’s not that the body can’t down-regulate this gene – it’s that it doesn’t – or else there are factors that up-regulate it during aging.

  2. Are there any known humans born with an MYC+/- status? We would expect them to be rare, since MYC-/- means early death, but not absent. If there are such people, does the +/- condition express in other ways? Are they perhaps less handsome or virile, for example?

    • It’s unlikely that a mutation would cause the MYC gene to be completely missing (+/-) but it’s quite possible that a mutation could cause the gene to be dysfunctional, and effectively missing. If this caused a disease, we would probably know about it by now. If it affects humans the way it affects mice, it’s unlikely that anyone with this rare genetic condition would ever be identified or their genome scanned for mutations.

  3. “Many anti-aging measures have tradeoffs. Mice given rapamycin, for instance, have increased cardiovascular disease risk”

    I haven’t seen studies showing this (“dyslipidemia”, yes; cardiovascuclar consequences, no). What I’ve found are papers like these:

    Rapamycin Attenuates Atherosclerotic Plaque Progression in Apolipoprotein E Knockout Mice: Inhibitory Effect on Monocyte Chemotaxis

    Inhibition of mTOR Signaling With Rapamycin Regresses Established Cardiac Hypertrophy Induced by Pressure Overload

    Oral rapamycin attenuates inflammation and enhances stability of atherosclerotic plaques in rabbits independent of serum lipid levels
    ————-
    Also, papers on rapamycin as a cancer preventative and therapeutic agent, contrary to expectations.

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