Aging and Disease: 2.5 Cell Senescence, Changes In Molecular Turnover, Most Molecules

• Aging
• mitochondria

As the human body is composed of cells, so are cells composed of molecules. It is true that the cell encompasses a plethora of organelles (membranes, mitochondria, nuclei, Golgi bodies, ribosomes, etc.), but each of these organelles is in turn composed of pools of various molecules. Just as cytoplasm is a “soup” of molecules, organelles are also collections of molecules. The precise types of molecules, their numbers, and their rates of turnover vary from organelle to organelle. The most common molecular types are lipids and proteins, but with admixtures of other molecules, such as carbohydrates (such as sugars), as well as hybrid molecules, such as glycolipids and glycoproteins. As you’d guess, the complexity not only doesn’t stop there, it barely begins there. To talk of a few simple molecular types is only a fuzzy, naïve sketch of that complexity involved in living cells. We’ll look a bit deeper at t he molecular types, then take a simpler view and focus on the only critical feature in aging cells, namely molecular turnover.

Looking at the cell as a whole, the typical human cell is (by numbers) about half lipid molecules and about half protein molecules. Most of the lipids are in membranes (such as the cell membranes, the mitochondrial membranes, and the nuclear membranes); most (but by no means all) of the proteins are in solution in the intracellular fluid. While the membranes have far more lipid molecules than protein molecules, the proteins are heavier (and larger). So while lipids are more numerous (about 50 x as numerous) than proteins in the membranes, the mass of the lipids and the proteins (as well as glycoproteins, etc.) are about equal.

While the lipids determine how the membrane acts in a general sense, it’s proteins that determine the functional (and the active) properties of the membrane. So while there aren’t as many protein molecules, but what they lack in numbers they more than make up for in their importance to cell activity. What about cytoplasm? About 40% of body weight is made of the intracellular fluid, where lipids are heavily outnumbered. In the cytoplasm, it’s the proteins, the electrolytes, and other molecules that determines the activity.

While proteins (as well as glycoproteins, etc.) come in thousands of types, even the lipids are a complex family. The most commons lipid molecules are phospholipids, but there are also cholesterol molecules (sometimes as numerous as phospholipids) and glycolipids, which are sugar-lipid molecules, especially common on the outer cellular. To make things even more complex, some molecules are complex conglomerates of both proteins and lipids.

That’s the introduction to the complexity, but from our standpoint – aging related disease – the important point is not the types of molecules or where they are, but the observation that all of them – every molecule we’ve mentioned – is in continual flux. All of the thousands of different types of molecules are being actively recycled. This is true whether we look at lipids or proteins, organelles or cytoplasm, intracellular molecules or extracellular molecules, molecules of a single type or compound molecules. They all being actively recycled. To be specific, none of them sit around for your lifetime, but all of them are being replaced on a moment-to-moment basis. With the sole exception of DNA, none of the molecules repaired. Instead, they’re simply recycled.

Some of these molecules are recycled slowly, some are recycled quickly. In the case of aerobic enzymes in your mitochondria, where the damage rate is high, these molecules are turned over rapidly; in the case of come cholesterol molecules, where the damage rate is lower, the molecules are turned over more slowly. While you might guess that “damaged” proteins are tagged and turned over more quickly, the reality is that ALL of your proteins – even those that are 100% perfect – are continually recycled. This turnover, proteolysis, is not just a passive “recycling” but is actively regulated and fine-tuned, and is part of the cell cycle and cell division, gene transcription, and general cellular quality control. Where we once viewed proteins a stable molecular pools that were subject only to “wear and tear”, active molecular turnover has been proven by isotopic studies. There is a basal rate of molecular turnover, specific to each protein and each lipid, which occurs regardless of damage: in any given molecular pool, molecules are degraded and replaced whether the molecule is normal or not. However, the rate of degradation can go up or down, depending on the rate of damage. For example, ubiquitin conjugation to globin molecules is markedly enhanced by denaturation of hemoglobin, so although hemoglobin undergoes “recycling” regardless of damage, the rate of that “recycling” goes up in the case of molecular damage.

Not only does this permit fine control of cell functions, but it is the only way to ensure quality control as well: the faster molecules are turned over, the more likely the molecules are to be undamaged and capable of doing their jobs. As we saw in the last blog, the slower the turnover, the higher the percentage of dysfunctional molecules. If we think of this recycling process as cell maintenance, then the slower the maintenance, the less functional the cell as it becomes clogged with molecules that don’t work.

Proteins, lipids and other molecules are turning over continuously and extensively. The turnover of each individual type of molecule is specifically regulated and varies with cell conditions and over time. The regulation of cell processes is not merely controlled at the transcriptional or translational levels, but is finely regulated at the level of protein degradation as well.

How fast do these molecules turnover? Proteins have half-lives varying from a few minutes to several days. The rate of turnover varies depending upon the protein, available nutrients, hormone levels, and especially by cell aging.

But if molecular recycling requires metabolic energy, then why does the cell engage in molecular turnover at all? They answer is to avoid the accumulation of damaged and dysfunctional molecules. It’s much like asking why a home owner spends money on the upkeep of their house. Both the home owner and the cell must spend (money or energy) in order to maintain function. The more they spend, the higher the quality of the house on a day-to-day basis. The less they spend, the more likely the house (or the cell) is to fall apart.

The key observation, from the standpoint of aging and age-related disease, is that almost every molecule we look at shows a deceleration of turnover as cells age. Lipids, proteins, and other molecules sit around longer. The result is leaker membranes, less effective DNA repair, dysfunctional mitochondria, and a host of other gradually increasing failures in the aging cell.

Next time: 2.6 Cell Senescence, Changes In Molecular Turnover, DNA Repair