Sweet, short life on a sugary diet

Imagine you are a tiny little worm, happily feeding on bacteria, and also got lucky to have some steady sugar added to your diet. Everything looks - or, should we say, tastes - great ... until it's time to go. The bad news is that for you death comes 3-4 days sooner than for your counterparts without extra sugar in their diet; they get to live all of their 18-day lifetimes.

This is a true story: it actually happened to undisclosed number of C. elegans (Caenorhabditis elegans, or roundworm), in an experiment by Dr. Cynthia Kenyon, molecular geneticist at the University of California, San Francisco. Worms who had small amount of glucose added to their daily diet, had their lifespan cut short by about 20%.

What did sugar do to them? A simplified scheme may look like this:

◊ elevated blood glucose level stimulates production of insulin, needed for its entry into the cells

◊ cells moderate overflow of glucose by developing lowered sensitivity to insulin

◊ this further elevates both glucose and insulin blood levels, but cells' glucose supply may become insufficient due to their insulin insensitivity

◊ chronically elevated insulin level creates complex signals affecting multiple metabolic pathways; among the consequences seen on C. elegans was downregulation of glycerol-transporting aquaporin channels (aquaglyceroporins), possibly restricting this alternate cellular fuel source as well

◊ insulin signaling pathways include effects on genes, as well as special proteins - so called transcription factors - controlling gene expression; elevated insulin level promotes higher oxidation states, while reduced insulin promotes protective, stress-resistant metabolic states akin to those of dauer (hibernation-like mode of worm's existence during development induced by unfavorable conditions), but without actually going into it

The key gene involved in dauer-related processes in the worm is
Daf-2 (Dauer formation 2) gene, which does it by modulating endocrine signaling. It is, however, only one of the players involved; to exert its influence, it needs coordinate action of other regulatory proteins downstream, such as Daf-16, and HSF-1 heat shock factor. Worms without these two proteins were not affected by elevated glucose level.

In fact, it is a set of genes upregulated by Daf-16 that are directly involved in life extension. When their activity is purposely inhibited, the result is up to 20% reduction in lifespan, without exposure to elevated glucose levels.

On the other hand, suppressing Daf-2 activity will

more than double worm's average lifespan -

as Kenyon's studies from 1990s show - but not if glucose is added to its diet. Obviously, the final outcome is determined by the specifics of individual biochemistry, both, those significantly influenced by environmental factors (i.e. elevated glucose intake), and those that are not.

So how this worm story relates - if at all - to us humans?

Well, we're not all that different. Worm's Daf-2 gene is its lone member of the insulin receptor family; it belongs to the same family that our insulin receptor (IR) and insulin-life growth factor receptor (IGF-1R) do. To a good extent, its functions overlap with those of the other two.

Worm's Daf-16 gene, downstream from Daf-2, is a FOXO protein subgroup member. FOXO proteins are gene transcription factors belonging to the Forkhead Box, or FOX family of proteins, with the "O" subgroup sharing the characteristic of being influenced by the insulin/PI3K/Akt signaling pathway. The FOXO protein transcription factors in mammals, including humans, are FOXO 1, 3, 4 and 6. They were first identified in human cancer cells. Their basic functions is to

modulate genetic activity according to environmental inputs.

Activity of both, Daf-16 and mammalian FOXO proteins is directly influenced by the insulin/PI3K/Akt signaling pathway. Akt (serine-threonine kinase activated by PI3K, phosphoinositide 3-kinase or PDK1, phosphoinositide-dependent kinase 1) mediated phosphorylation of the FOXO proteins, resulting from intensified insulin and/or insulin growth factor signaling, causes them to move from cell's nucleus to the cytoplasm, preventing them from transcribing to their target genes.

Phosphorylation of FOXO proteins by other protein kinases (kinase=type of regulatory proteins), like JNK and Mst1, as a response to increased oxidative stress, has the opposing action, causing FOXO proteins to move from cytoplasm to cell's nucleus, where they can transcribe to their target genes.

What is it, exactly, that they do?

FOXO proteins modulate expression of genes regulating vital cellular processes like apoptosis (programmed cell death), cell-cycle progression, and oxidative protection, by activating free radical quenchers catalase and manganese-dependant superoxide dismutase (MnSOD) and by facilitating DNA-repair process. They are also involved in cellular differentiation, glucose metabolism and energy homeostasis, even in upregulation of neuropeptides in hypothalamus. More on their functions is to come, as more FOXO proteins target genes will be identified.

To make long story short,

you don't want your regulatory FOXO proteins possibly
kicked out of the nucleus due to chronically elevated
glucose levels.

They're too important.

The activity of worm's FOXO protein, Daf-16, prolongs lifespan by modulating gene expression toward increased resistance to oxidative stress, DNA damage and pathogens (bacteria that the worm eats ultimately overwhelm and eat up the worm; worms on glucose-enhanced diet get weaker and eaten up sooner). Inhibiting worm's insulin receptor, Daf-2, or PI3K, results in up to tripled lifespan - but only when Daf-16 is active.

In mice, inhibiting functions of insulin receptor or insulin growth factor 1, both downregulating mammalian FOXO proteins - and more so when glucose level is elevated - results in up to 30% life extension.

Chances are, our longevity also benefits from FOXO proteins doing their job. And the seemingly innocent attraction to sweets - among other environmental inputs - may as well be triggering an archaic cellular response deeply imbedded into the "blueprint" of our cells, compromising their function and

making the body less efficient, more vulnerable and perishable.

In addition, the role of FOXO proteins in apoptosis, cell-cycle progression and DNA repair makes them a likely balancing force between two opposites with the same roots: cellular longevity and cancerous growth. As mentioned, they were first identified in cancer cells, at chromosomal translocations (i.e. fragments of broken chromosomes cross-linked to other chromosomes).

Knowing what we do about FOXO proteins function, they were there to help repair damaged DNA; the extent of damage indicates that too many of them were absent, sitting idle in the cytoplasm, possibly - at least in part - due to the chronically elevated glucose level.

Anyway, Dr. Kenyon took the short sweet lives of C. elegans very seriously. She dumped sweets and switched to low-glycemic diet. In her own words, she feels great now - as if she is a kid again.

Sugar is sweet, but life is sweeter...

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