Removing Dysfunctional Cells
Our cells have built-in programming that sometimes veers them far away from their normal fate. Some of this programming watches out for conditions emerging within the cell that could put the rest of the body at risk; similar systems exist because the body no longer has need for the function that the cell normally fulfils. Pushing these cells to undergo such transformations is favored by evolution because it meets short-term needs, and having a few of these abnormal cells in the body for is nearly harmless. But the number of these cells in our tissues gradually rises over time, until by our fifth decade or so they begin to reach levels that are harmful to normal tissue function. Examples include:
Classic Senescent Cells
The original and most well-studied sort of cells of this type are what are usually called “senescent” cells. Senescent cells began their existence skin cells, or as related cells that normally play supporting roles in other organs, but were forced into an abnormal state where they lost the ability to divide and reproduce themselves as a protective response to some danger. For instance, the senescence program is activated in cells that undergo risky changes in their DNA expression that put them on a path toward becoming cancerous; it is also activated in some cells involved in the wound response, to keep them from overstepping their bounds and generating an overgrowth of fibrous connective tissue.
But in addition to halting growth, senescent cells secrete abnormally large amounts of proteins that inflame the immune system and degrade the normal supporting tissue architecture. The relatively small number of such cells in a youthful tissue is so small as to be harmless, but after decades of accumulation, the number becomes large enough that their abnormal metabolic state begins to pose a threat to surrounding, healthy tissues. Larger numbers of senescent cells in a tissue make it more vulnerable to the spread of cancer, contribute to inflammation, and skew the local activity of the immune system.
Cells in Fat Tissue
It’s well-known that people lose muscle mass as part of the degenerative aging process; it’s much less understood that fat mass, too, begins to decline in the fourth decade, albeit more slowly – and it’s a decline that can’t be explained just by reduced energy intake. But the process is uneven, leading to relative increases in fat tissue in some places even as other places lose nearly all of their fat. In the process, fat tissue begins to behave abnormally, releasing large amounts of signaling molecules that cause inflammation and make the body more resistant to the hormone insulin. These age-related abnormalities then drive a range of unhealthy metabolic changes, including a reduced ability to move blood sugar out of the blood in response to the hormone insulin.
But the the reasons why fat tissue goes haywire during degenerative aging do not lie in the fat cells per se (adipocytes – the ones that store up excess Calories). Instead, the culprits are two other kinds of cells that reside in fat tissue: preadipocytes and visceral adipose tissue macrophages (ATMs). Preadipocytes are the precursor cells from which fat cells are formed. They begin to behave abnormally in all people during degenerative aging, whether they are slim or overweight: their expression of their genes becomes altered; they release more inflammatory factors; and they fail to reproduce themselves and to develop into mature fat cells, which may be one reason why the level of unhealthy free fatty acids circulating in the blood rises with age. Aging preadipocytes also develop a large droplet of abnormally-stored fat molecules within themselves, which may be part of why they and their progeny become more insulin resistant than the corresponding cells in young people’s fat tissue.
The other unhealthy change in that occurs in fat tissue over time occurs in the so-called visceral fat – the fat tissue that surrounds the gut and liver. It’s become widely understood that most of the metabolic harm that occurs as a result of obesity is the result of having too much fat in the visceral depot in particular (making people “apple-shaped” rather than “pear-shaped”). The degenerative aging process leads to a higher percentage of one’s total fat being shifted into the visceral fat tissue, as well as into aberrant storage in the muscles and the liver.
It’s less well-appreciated that the reason why excess visceral fat is so metabolically toxic is that it causes the accumulation of a kind of immune cells called adipose tissue macrophages (ATMs) to multiply in the visceral fat tissue. This may be an attempt by the immune system to clean up the wreckage from bloated, dying fat cells when excessive amounts of energy are stuffed into the local adipocytes and the has a harder time providing an adequate blood supply. Like senescent preadipocytes, ATMs are also highly inflammatory cells, and their accumulation in visceral fat is probably one key reason why obese people become insulin resistant even when they have not yet undergone other degenerative aging changes. It is also possible that degenerative aging itself has effects on the function of ATMs that go beyond those attributable to the sheer mass of visceral fat and number of ATMs in the tissue.
CD8+ T-cells (or killer T-cells) are a kind of immune cell that specializes in destroying cells that have been hijacked by viruses or by cancer. Killer T-cells first emerge as naïve cells that are out on the lookout for entirely new threats, but in order to do their job, they must assume a specialty, being trained by other immune cells to recognize, seek out, and eliminate a very particular threat. But while the total number of invaders that the body has encountered increases with every year of life, the total number of killer T-cells cannot: the sum total of all the different specialized cells, plus the naïve cells, is held constant over time. So an increase in the number of killer T-cells with one particular specialization can only come at the expense of a decrease in cells with different specializations (and naïve cells).
As part of the degenerative aging process, an imbalance in the killer T-cell population occurs. Specific subsets of killer T-cells refuse to cull their numbers to make room for other subsets, and instead begin to occupy more and more of the limited immunological “space” – literally crowding out cells that are equipped to fight other infections. This crowding-out effect is thought to be one of the main reasons for the weakened immune responses of people as they age, which is why so many people over the age of 65 die or are hospitalized each winter by influenza or pneumonia, while younger people can bounce back after a couple of days in bed. This crowding-out effect is also one reason why vaccines are less effective in older people than in younger: there are fewer naïve cells available for the vaccine to “teach” to recognize the new threat.
Each of these various kinds of abnormal cells occur in different tissues, and the problems they cause are distinct from one another. Still, the same basic strategy can be used to eliminate the harmful effects of all of them, which is to destroy the cells themselves. There are two main approaches that could be used to achieve this:
- Develop a drug that is toxic to the unwanted cells, or that makes them commit suicide, but that doesn’t harm healthy, normal cells; or
- Stimulate the immune system to selectively seek out and kill the target cells.
The most likely way to selectively target these abnormal cells would be to make use of the distinctive molecules that occur on their surfaces. Luckily, different cell types tend to have different things on their surfaces, which play particular parts in their specialized roles in the tissue, so it is a matter of identifying and targeting cell-surface markers that are specific to these abnormal cell types.
This strategy is already the basis of some cancer therapies, which shut down their targets’ growth or to attract immune cells to destroy them. Some such markers are already known for anergic killer T-cells and for ATMs, so it is a matter of investing the time and effort to develop a panel of such markers that identify them definitively, and then developing a cell-destroying system to go with it.
There may also be opportunities to make it easier to target and/or destroy anergic T-cells as part of building an impregnable defense against cancer. Should the OncoSENS strategy indeed prove to be the only ultimate safe haven against this terrible disease, then part of the comprehensive panel of rejuvenation therapies will be the replacement of the cells that give rise to T-cells with pristine, re-engineered cells impervious to cancer. But if we are already committed to this step, then it is a very small matter to engineer the replacement cells with additional features that make them susceptible to ApoptoSENS therapies when they become anergic.