For more than a decade, Claudia Cavadas of the Center for Neuroscience in Coimbra, Portugal has been on the trail of a signal molecule that comes from a region of the brain associated with timing.  It’s a small protein called Neuropeptide Y, and Cavadas has recently collected the body of evidence that it is a central determinant of aging in the brain and throughout the body.  Whether or not NPY proves to be the Philosopher’s Stone, I think she’s on the right track to be investigating neuroendocrine origins of aging.

The present column also contains a (belated) update on ALK5 and TGFβ.

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Since the genetic science of aging began to take off in the 1990s, the biggest surprise has been the extent to which aging is centrally orchestrated. ”Regulated” is the accepted word, but I don’t hesitate to say “programmed”.  For those of us interested in intervening to slow or reverse the process, the burning question is: how is the program implemented?  If the process is centrally orchestrated, where is the orchestra’s conductor?  

We have the same genes when we are old as when we are young, but different genes are turned on and off in different stages of life.  How genes are turned on and off is the science of epigenetics, and we are just beginning to untangle the set of chemical add-ons that bind to the chromosome or to the histones, protein spindles around which the chromosome is spooled.  Chemical signals that turn whole suites of genes on and off are called transcription factors, and these can be big molecules or small, proteins or RNAs, very specific and targeted to a single gene, or aimed more generally at large swaths of the chromosome.

At the least, transcription factors are able to regulate the body’s rate of aging.  But I see evidence that the chemical signals have even more power—the chemical signals tell the body how old it is.  Change the signals, and the body can change its age.

When we think this way, the questions “what are these signals?” and “where do they come from?” become exciting and highly charged.  The most intuitive and logical place to look for a source of age signals is in the brain.  Here are four reasons to look to the brain’s hormone center, the neuroendocrine region, as a source of aging signals.

• We know that aging is highly plastic and adaptive depending on behavior and environment.  To sense many factors and make a decision about aging, it seems that the combined forces of the nerves and endocrine signal transducers in the brain are best equipped for the job.
• The hypothalamus is a neuroendocrine region of the brain already known to house the seat of the 24-hour clock that synchronizes our circadian rhythms, the suprachiasmatic nucleus.  
• The hypothalamus is also responsible for flooding the body with at least one of the transcription factors that increase destructive inflammation late in life (NFkB).
• In a worm experiment fifteen years ago, genes for aging were modified in different systems of the worm, and the modifications were effective in changing the worm life span only when the genes were modified in the nervous system (not in skin or muscle or digestive system).

This mode of thinking suggests that Cavadas has been digging at the taproot of aging, and that the signal she has identified may be of central importance.  In a recent paper, Cavadas lays out the case for a central role in Neuropeptide Y in dictating the age of the body.  

Accumulating evidence suggests that neuropeptide Y (NPY) has a role in aging and lifespan determination. In this review, we critically discuss age-related changes in NPY levels in the brain, together with recent findings concerning the contribution of NPY to, and impact on, six hallmarks of aging, specifically:

• loss of proteostasis
• stem cell exhaustion
• altered intercellular communication
• deregulated nutrient sensing
• cellular senescence, and
• mitochondrial dysfunction

NPY is a small protein, with 36 amino acids, found in the nervous systems of all higher animals.  It is one of the most abundant neuroendocrine proteins, but since these chemicals are very powerful signal molecules, the body’s total inventory is measured in μg (millionths of a gram).  NPY has various roles related to appetite, anxiety, memory, and circadian rhythm.  Levels of NPY decline with age, especially in certain regions of the brain.  Caloric Restriction also elevates levels of NPY.  High blood sugar levels tend to inhibit NPY.  And there is a bit of evidence that NPY is necessary for CR to extend life span:  Mice in which the NPY gene has been knocked out don’t respond to CR. NPY is also associated with cancer suppression in mice.

Autophagy is the process by which cells break down and recycles damaged molecules.  As we age, autophagy slows down and damaged molecules accumulate:  misfolded proteins, cross-linked sugars, lipofuscin and amyloids.  A central function of NPY is in promoting autophagy, especially in the brain.  

The NPY gene can be read in a way that transcribes only the second half, and the result is a protein that binds to mitochondria and improves energy efficiency, reduces ROS damage.  Some studies suggest that NPY can extend the useful life of stem cells, and delay cellular senescence.  Links to anti-inflammatory chemistry are less well established.

 

Why NPY probably is not the Philosopher’s Stone

All this suggests a role for NPY in aging, and the possibility that increasing NPY might increase life span.  But it is not easy to increase the body’s transcription of a target protein.  (It is easier to block a protein that is bad than to promote one that is good.)  And my guess is that we will find signals further upstream from NPY that are even more effective points of intervention.  The guess is based on the fact that NPY is a neurotransmitter, an “end-use” molecule.  I suspect that the upstream source of aging will be found in transcription factors, the molecules that bind to DNA and determine which genes are expressed.

 

Other Signal Molecules from the Brain

TGFβ might be a good candidat for the first brain signal to become a target for anti-aging therapy. TGFβ is a not a transcription factor but a cytokine, a signal protein that affects the energy metabolism and, in particular, inflammatory response.  It comes not from the hypothalamus, but from the hippocampus, another part of the brain, an inch or two underneath.  TGFβ works against us, i.e., we produce more and more of it as we age, and it rallies the inflammatory legions that promote arterial diseases and cancer.  We would want to block its action, and that might not be too difficult.

One of the targets, receptors into which the TGFβ molecule plugs to do its work, is called ALK5.  Jamming ALK5 has been promoted by the Conboy lab at Berkeley and others as a strategy to test further.  ALK5 inhibitor can be injected deep into the body cavity, where it has already been shown to promote new growth in both muscles and nerves in mice.  This function is apparently related to its role as antagonist to TGFβ.  Remarkably, stem cells retain their ability to regenerate new tissue well into old age, but they receive signals telling them to stand down.  Simply changing the signaling environment can make an old stem cell act young.  This has been a major theme of the Conboys’ work.

What good is TGFβ?  The story is complicated.  The molecule can apparently be pro-inflammatory or anti-inflammatory, also pro-cancer or anti-cancer.  This relates to the GDF11 controversy, too.  GDF11 is in the TGFβ family.  To me, the Conboys are a trusted source, and they have systematically built a case that too much TGFβ in later life is a big factor leading to more inflammation and less stem cell activity.

Their ALK5 inhibitor has only been tested for short-term benefits.  The next step is to do life span studies in mice with ALK5 inhibitor.