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Biological systems are pretty good at measuring fairly long times, for example, menstrual cycles (month), or puberty (years). Counting days or years seems to be implausible, and chemical concentration also seems implausible. What are the physiological processes that are involved in keeping track of such long periods? Is it just a long sequence of finite state changes?

I understand there are environmental correlates such as seasonal changes and relative position of celestial objects to measure the relative time, but regardless of these external cues, I suspect that a pretty good internal clock for longer time scale could exist. For example, the time to menopause can actually be thought of as a counting mechanism of a shorter clock which is the menstrual cycle. But, how does the body know when to stop growing? I cannot think of biological processes with such long time constants that is stable.

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So your question relates to successful and timely development and maturation of an organism? And how is this regulated? –  Luke Sep 19 '12 at 11:51
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The short answer is: we do not know exactly, although we do have some insights.

I will take the example of puberty.

Although a clear definition of puberty is lacking, it is quite clear that it corresponds to a period where gonadal function starts.

This, in turn, is derived from the activation of the gonadotropin system, which consists of two main cell types:

  1. a small number of neurons located in the preoptic area of the hypothalamus (a nucleus at the base of the brain) called the GnRH neurons. GnRH is the Gonadotropin-releasing hormone, a small peptide that stimulates the production of gonadotropins from the pituitary.

  2. the gonadotrophs, a specialised group of cells in the pituitary (a gland located underneath the brain) which produce two hormones, called luteinizing hormone (LH) and follicle-stimulating hormone (FSH) which stimulate the gonads to produce various hormones, such as estrogen.

In mammals, the secretion of GnRH, and thus LH/FSH varies during the course of the menstrual/estral cycle. This cyclicity lasts several days (4-5 days in rodents, ~1 month in humans) and entrains the cyclical secretion of estradiol (E2) from the gonads.

Note that this is a sort of self-sustaining cycle, as cyclic levels of E2 will then allow for cyclic GnRH secretion and so on.

But, back to your question: how does the GnRH/LH/E2 system "wake up" at puberty?

The exact mechanism is still unknown, but recent work has found an important mediator, called kisspeptin, that is produced from two population of neurons in the hypothalamus, called the kisspeptin neurons.

Kisspeptin has been shown to be a very potent activator of GnRH neurons and work in the mouse has shown that these neurons appear at the time of puberty, their number increasing dramatically between 25 and 31 days (puberty is at around 30 days in mice).

Postnatal Development of Kisspeptin Neurons in Mouse Hypothalamus; Sexual Dimorphism and Projections to Gonadotropin-Releasing Hormone Neurons - Clarkson and Herbison - Endocrinology, 2006

Similar work exist in the monkey: Increased hypothalamic GPR54 signaling: A potential mechanism for initiation of puberty in primates - Shahab et al. - PNAS, 2005

In humans mutations in either kisspeptin, or its cognate receptor GPR54 results in disturbances of pubertal maturation because of underactivation of the system (hypogonadotropic hypogonadism) or hyperactivation (precocious puberty).

So, now the question is shifted: why do kisspeptin neurons show up only at puberty? We don't know for sure, but it looks like increased levels of E2 could be important for this.

Again, we get into a self-sustaining cycle. Growth of the body generates an increase in E2 production (possibly due to increased volume of the gonads?), which, when over a certain level permits the development of kisspeptin neurons, which will then stimulate the GnRH neurons, resulting in increased LH and E2. We then have more E2 and this makes kisspeptin neuron grow even more etc etc.

Kisspeptin system maturation
From: Postnatal development of an estradiol-kisspeptin positive feedback mechanism implicated in puberty onset. - Clarkson et al. - Endocrinology, 2009

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Though chemical concentration seems implausible, at the deepest level it is the cause.

On a smaller scale - how does a eukaryotic cell know when it is ready to divide? By the concentration of different cyclins and CDKs. They are produced all the time, in amounts dependent on the general availability of nutrients, but they are used at different times. Some are used during DNA synthesis, so that if they are present, the cell "knows" that there is not enough DNA to divide itself; others are used during cell division, so a freshly divided cell "knows" that there is a long period before next division. How do our hairs grow at seemingly same intervals? Because their location was decided on the basis of concentrations of certain proteins or small molecules when skin was just being formed (I don't have Developmental Biology right here, so no protein names, sorry).

The menstrual cycle is regulated by the concentration of the hormones and ovulation triggers changes leading to menstruation. That's why menstruation happens 14 days after ovulation and not just 28 days after the previous one - if a woman has a 30 day-long cycle, her ovulation will be on 16th day of the cycle. Menopause generally happens when the supply of eggs ends and they stop providing cues about the proper time for menstruation.

The cues about puberty and aging may be more subtle. One well-known cause of aging is the shrinking of the telomeres, the ends of the chromosomes. Cells with short telomeres can't divide. Too low of a "concentration" of these telomeres "tells" the cell that it is old.

Another well known fact - malnourished girls don't go through puberty and malnourished women stop ovulating. Low food "concentration" is a sign of a bad time to burden your body with nourishing and feeding a baby.

Detailed mechanisms behind those processes are often different, but the general rule is the same: each process has threshold(s) for certain chemicals; if they are exceeded, the organism reacts.

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I think you sort of have 2 answers here - chemical concentration and chemical modification. there are only 2 copies of the DNA in most metazoan cells - that's not really concentration. Epigenetic effects like this more akin to computer memory. If one or two copies of a gene are marked, it will behave differently. –  shigeta Sep 19 '12 at 14:24
    
What I meant was that in G1 there is just one copy of the whole genome, so not enough to divide between two daughter cells. During S phase the second copy is produced (and some cytokines and CDKs used), so that during G2, when cytokines and CDKs necessary for cell division are accumulated, all the time there are two copies of the genome - enough to perform a cell division. Sorry about the misleading description, I found this place only today and haven't been using my Molecular Biology Explaining Skills in 2 or 3 years. I'll be better :) –  jkadlubowska Sep 19 '12 at 17:10
    
no worries - just trying to draw out a distinction... –  shigeta Sep 19 '12 at 17:35
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There has been some recent advancement answering this question, especially in terms of puberty. Here are some quotes from the news article about it.

The timing of puberty onset is highly variable and ultimately mysterious.

So, our understanding is pretty limited.

Contrary to popular belief, however, puberty is not a simple developmental progression of maturation of the reproductive axis, as this system is fully mature long before puberty and, in fact, must be suppressed during a period called the juvenile hiatus. The key component of the axis is the gonadotropin-releasing hormone (GnRH) neuron.

But, how is GnRH controlled temporally?

The authors have thus established that epigenetic repression of at least Kiss1, and probably other genes, mediated indirectly through the PcG family of transcriptional repressors, is the brake on the hypothalamic-pituitary-gonadal axis that must be released for puberty to proceed. More importantly, an epigenetic regulator provides the perfect interface for coordinating the genetic and environmental influences that are known to buffet this process.

This is just one piece of the puzzle as the title of the news article says, and there are still a lot of gaps in our understanding.

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