Anti-Aging Medicine: Two Paths Diverge

…and sorry I was I could not travel both.

  • Aging is an accumulation of damage.  If we want to return the body to a more youthful state, we’re going to have to repair that damage.
  • The body never forgets how to be young.  Given the appropriate signaling environment, the body will restore itself to a youthful state.

The future of medicine is the future of anti-aging medicine.  I don’t think anyone seriously disputes this.  Infectious diseases are a minuscule problem compared to a century ago, and with hygiene, good public health practices, and responsible restraint in applying antibiotics, we may hope to avoid a return to the days when tuberculosis and syphilis were pandemic.  We are fast learning to treat congenital disorders, and safe gene therapies are already being tested.

This leaves diseases of old age as the next frontier.  To slow the progress of aging, there is no doubt that signaling approaches work in animals, and will work (probably with less efficacy) in humans.  Caloric restriction (CR), exercise and other forms of hormesis are the best approaches we know at present.  Pills (e.g. metformin, berberine) may offer some of the benefits of CR without the hunger, and an “exercise pill” has been proposed.

The next step is to actually reverse aging, to restore the body to a more youthful state.  Among those of us who advocate research in the technology of age reversal, there are two prevailing paradigms.  I am with the school that says the same signaling approach can be extended to trick the body into thinking it is younger than it is, and the body will renew its cells and replace damaged biomolecules on cue.  The other school says that once the toothpaste is out of the tube, it’s not going back in.  We will have to engineer prosthetics, use bioengineering and regenerative medicine to replace body parts that have worn out.

Theory

“Everything degrades over time–it’s basic physics”

This is just wrong, but it’s so prevalent (among gerontologists and the great unwashed masses alike) that I’ll refute it yet again:  There is no physical necessity for aging.  Analogies to wearing out and to chemical corrosion are flawed and misguided.  The body may accumulate more damage than it repairs; but it may also repair more damage than it accumulates.  The choice is made by the metabolism (as programmed by evolution), not by physics.

  • The Second Law of Thermodynamics is specifically about closed systems, meaning systems that don’t interact with the outside world.  But living beings are evolved to take in order from food or sunlight and dump entropy back into the environment.  All of life is an end run around the Second Law.
  • Still, some people say the “end run” has to come to an end some time.  How can repair be “perfect”?  Well, it doesn’t have to be perfect. There is nothing perfect about a 20-year-old body, and it is the body’s metabolic choice whether to build itself ever stronger, more resilient and less vulnerable to disease, or allow it to decay, or (in between) to maintain a constant level of youthful robustness indefinitely.
  • …and indeed, some animals and many plants do go on getting stronger and larger, with lower and lower mortality risk, year after year after year.  This is called negative senescence, a fancy word for aging backwards.  Most trees do it, as well as lobsters, clams, some turtles, and possibly sharks and whales.
  • If physics demanded that living organisms always degrade then growth and development would be impossible.

Evolutionary biologists almost all appreciate this—aging is a problem for evolution, not for physics.  Though many of the symptoms of old age may look like accumulated damage, there is no necessity for the damage to accumulate; the body is making a choice to repair the damage only partially, as opposed to rebuilding better-than-new, which is perfectly possible, both physically and biologically.

More detail is in my blog post from 2014.  Here is an academic paper on the subject.

“If the body could rejuvenate itself, it would already have done so.”

This is also a common view, and harder to dispel.  I think it is just as wrong as the one above, but full disclosure compells me to admit that I’m still in a minority on this question.

Since the 1960s, Nature has become an object of reverence, especially among the secular quarter in Western culture, people who are skeptical of religious dogmas.  The myth is that evolution has worked for millions of years to perfect the individual, and that human intervention is more likely than not to trip over the law of unintended consequences.  Biochemistry is not only highly optimized, it is also highly intricate and every biochemical plays multiple roles.

Like most myths, this one carries some truth.  A lot of Western medicine treats symptoms, not causes, and has questionable value in the long run.  Human attempts to “manage” nature have been fraught with rude surprises.  And a natural diet of vegetables and fruits is a much better starting place for healthy nutrition than is a diet of processed food.

But “natural medicine” can never reverse aging.  The problem is that we are not just evolved to be strong and fertile individual competitors, but we are also evolved to be part of a stable ecosystem.  Aging was bequeathed to us by evolution, not for our sake as individuals, but as a way to stabilize ecosystems.  Individuals need to die on a schedule that is internally determined because if we left the matter of death to the world outside, then starvation would be the principal cause of death, and starvation tends to take everyone down at the same time.  This is called “extinction”.  The population can’t afford to eat whatever is available and die only when the food runs out, because then everyone would die at once.  The population would swing wildly up and down.  Evolution has taken pains to protect our species from extinction, just as surely as she has taken pains to make us individually tough and resilient and fertile.

When it comes to aging, we can’t assume that “we tinker with evolution’s product at our peril, because evolution has already done her best to make us live as long as possible.”  In fact, the body’s repair mechanisms slow down as we get older (just as we need them most).  The immune system goes haywire, failing to attack pathogens but turning on the self (arthritis, diabetes).  Healthy nerve and muscle cells commit suicide (Loss of nerve cells is part of Alzheimer’s Disease; loss of muscle is called sarcropenia, a universal wasting disease.)

As we get older, the balance of signals in our blood changes in some ways that are random and some that are predetermined.  All the predetermined changes are detrimental; signals in the blood raise the level of inflammation, which is the most significant root cause of all the diseases of old age.

The idea that aging was programmed into us for the sake of the ecosystem isn’t just an abstract theory; the theory was devised to explain the reality that the aging body both shuts down repair mechanisms and turns on active self-destruction, in a way that looks quite deliberate.  All the principal mechanisms of aging have been preserved over the vast stretch of evolutionary time.

 

Examples of the Rebuilding Approach

Prosthetic limbs, artificial knees and hips are nothing new, but they do keep getting better.  Computer technology promises artificial limbs that can interface with existing nerves so that amputees can learn to control them.  When lenses in the eyes become clouded by cataracts, surgery to replace the lens with plastic have become routine.  Artificial eyes are now conceivable, and there are crude working models.  Mechanical hearts would be most useful, but the technology has been the subject of an intensive bioengineering program since 1969, while mortality rates remain stubbornly high.

Tissue engineers are working on techniques to grow organs on scaffolds.  Tracheas andbladders have already been implanted successfully in humans.

Despite impressive technological advances, the challenge facing this approach is formidable.  Things that go wrong as we age include clogged arteries, inelastic skin, and weak, degraded muscles.  These parts are not easily replaced.  Brain aging presents the ultimate challenge.  No one wants a prosthetic brain.  (Maybe I’m wrong about this.)

Aubrey de Grey and his SENS Foundation have prominently championed the repair-and-replace approach to geriatric medicine.  The current research program of the SENS Foundation (from their web site) includes

      • Engineering new mitochondrial genes
      • Fighting cancer by shutting down the cancer cell’s ability to maintain telomeres
      • Convincing the body’s immune system to attack amyloid plaques
      • De-fanging or eliminating senescent cells
      • Enhancing lipofuscin clearance
      • Engineering a new thymus
      • Epimutations in single aging cells
      • Finding amyloid in the heart
      • Quantifying extracellular crosslinks
      • Rejuvenating risk/benefit analysis
      • Rejuvenating the microenvironment
      • Repopulating the Gut
      • Scaling up glucosepane research

Four of the thirteen may be regarded as signaling approaches; the rest are conceived as building understanding and a technology of control at the molecular level that SENS hopes will ultimately be the basis for engineering aging out of the human metabolism.

 

Examples of the Signaling Approach

 

A growing number of anti-aging researchers are betting on the idea that we don’t need to repair everything that goes wrong with aging because the body can repair itself, if only we can rejuvenate the signaling environment.

FOXN1 rejuvenates the thymus

The slow disappearance (“involution”) of the thymus over a lifetime has been implicated in the age-related decline of the immune system.  The rebuilding approach seeks to replace the aged thymus with tissue engineering [ref, ref]; in contrast, the signaling approach seeks to stimulate the body to regrow the thymus on its own.  Of course, this is the easier approach, if it works.  Greg Fahy has reported success with growth hormone.  Several labs have recently reported hopeful signs that a signal protein called FOXN1 might be a specific trigger for regrowth of the thymus [ref, ref].

 

J147

Last week, a press release from David Schubert’s group in the Salk Laboratories in La Jolla made headlines for J147, a compound they have focused on more intently.  The world was introduced to J147 with a 2011 article in the high-profile journal PLOS One, which didn’t receive as much attention as it deserved.  There is a new article in the subsidy journal Aging that is getting more attention that it deserves.

The most notable thing about J147 is that it is a promising result from a new methodology for drug development.  Schubert’s lab began with curcumin, the active neuroprotective and anti-inflammatory component of turmeric.  Chemists synthesized and isolated hundreds of chemical cousins of curcumin, which were screened in cell cultures for neuroprotective activity at lower and lower doses.

In the end, the molecule J147 doesn’t look much like curcumin.

J147

Curcumin

Both molecules have two aromatic rings.  The curcumin molecule is mirror symmetric, which J147 is not.  And J147 contains fluorine, which no natural biomolecules do.  (Among popular drugs Prozac and Lipitor contain fluorine.)

The best ones were tested in rodents.  J147 improved memory in young mice and old.  In a mouse strain genetically engineered to be vulnerable something close to human Alzheimer’s disease, daily doses of J147 were able to delay onset of memory loss.  Even after the mice suffered memory loss, J147 was able to reverse it [ref from 2013]

The reason the new paper made more of a splash than the old was that it was framed in terms of general anti-aging benefits, rather than neuroprotection or memory improvement.  The new paper reports that mice on a lifelong regimen of J147 show generalized abatement of markers of aging as they grow older.  The work is promising, but it was all done with SAMP8 mice, genetically engineered to contract a version of Alzheimer’s disease, which usually kills them before they are a year old.  J147 has not yet been assayed for life extending potential in normal mice.

J147 is presently available in tiny quantities for a prodigious price.

 

ALK5 Inhibitors

Mike and Irina Conboy working at UCBerkeley have identified ALK5 as a pro-aging signal, and report success in rejuvenating tissues and whole mice with a molecule engineered to block the ALK5 pathway.  Their recent paper may be viewed as a manifesto for the signaling approach to anti-aging medicine.  It begins:

Stem cell function declines with age largely due to the biochemical imbalances in their tissue niches, and this work demonstrates that aging imposes an elevation in transforming growth factor β (TGF-β) signaling in the neurogenic niche of the hippocampus, analogous to the previously demonstrated changes in the myogenic niche of skeletal muscle with age.

This sentence is dense with meaning that is worth deconstructing.

Stem cell function declines with age largely due to the biochemical imbalances in their tissue niches,

The traditional view is that cells suffer damage with age.  Stem cells know they are old because of shorter telomeres.  They accumulate lipofuscin, and their DNA mutates over time.  Of course, aged stem cells cannot be as effective as young stem cells.  But the claim here is that the cells themselves are fine.  They are responding to signal molecules in the blood that tell them to lay down on the job.

elevation in transforming growth factor β (TGF-β) signaling in the neurogenic niche of the hippocampus,

The bad actor is fingered and, what is more, its source is traced to the hippocampus—a region of the brain known for neuroendocrine signaling, and implicated in other time-cyclic processes.

analogous to the previously demonstrated changes in the myogenic niche of skeletal muscle with age.

The Conboys had previously found that TGF-β signaling was responsible for inhibiting muscle growth in aged mice.

The article goes on to describe the receptor for TGF-β, one step downstream, that is responsible for the negative consequences of TGF-β signaling.  The receptor is called ALK5, and there are known molecules that can clog ALK5, blocking the signal pathway that has inhibited new growth in old bodies. “Very interestingly, both neurogenesis [new nerve cells] and myogenesis [new muscle tissue] were significantly enhanced in the aged mice treated with ALK5 inhibitor, compared to the animals receiving control buffer.”

ALK5 inhibitors are also available from lab supply houses, even more dear than J147.  But, to be fair, the molecule is more difficult to synthesize and the dosage is probably smaller.  (In fact, we have only theory to guide us for human dosages, since both these molecules have yet to be tested in humans.)

 

The Bottom Line

In the beginning, anti-aging medicine was thought to be fanciful, if not impossible.  How could human engineering improve on processes that Nature has been perfecting for a billion years?  Then a science of regenerative medicine began very slowly chipping away at that conventional wisdom, and a glimmer of hope pointed to promise of fixing the body directly with engineering, at least in the long run.

But a funny thing happened along the way.  There are indications in many areas that the body knows perfectly well how to rejuvenate itself, and we need only learn to speak the body’s (biochemical) language in order to say, “Have at it!”  A few people like me are pointing out that this contradicts everything we thought we knew about evolutionary biology, and that the “selfish gene” is in need of an overhaul.   But bench scientists are choosing to sidestep this theoretical debate and simply to do the practical thing.  They are pursuing a signaling approach because  it works.

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This article previously appeared in Josh’s excellent blog Aging Matters here. Republished with permission.