Fight Aging!

The environment surrounding our tissues and various complex systems such as organs incorporates a great deal of microbial life. We are surrounded by microbes, we have a whole cooperative ecosystem on our skins and another in our guts, and are constantly under attack by less friendly species. From the point of view of a great many classes of microbial life, we mammals are just another resource to be exploited as a basis for unfettered replication. Before the advent of modern medicine, life expectancy was largely determined by infectious disease and other environmental pathogens rather than the fundamental processes of aging. In the research paper linked below, the author makes a valid point, which is that we haven't really yet defeated the hostile microbes arrayed against us, just postponed their inevitable victory by decades for most individuals. When we consider aging, we should think about aging in the context of our vulnerability to the microbial world in addition to the failure of our component parts for other reasons.

This is really, I think, a type of argument for putting the age-related decline of the immune system at the top of the list of things to address when it comes to building rejuvenation therapies. I don't necessarily disagree, but it may be that our present state of knowledge makes it easier for us to join the dots between immunosenescence and inflammaging and all of the harm an age-damaged immune system causes, coupled with it being harder to quantify the specific contributions from other causes of aging. Now that senescent cell clearance is getting a whole lot more attention, for example, people are finding all sorts of links to specific age-related diseases and disease processes. When you can actually do something about a cause of aging, such as by clearing senescent cells, it becomes very much easier to find out how much harm they produce. Remove those cells and measure the outcome. Those experiments are ongoing at the moment, and a great deal is being learned. In the case of immune aging, there are several decades of good studies that compare various degrees of impairment of the aging immune system, and the role of inflammation in particular in aging is very well studied. The immune system plays many important roles beyond defense against pathogens, involved in everything from wound healing to destroying senescent and cancerous cells. All of these roles suffer due to the growing disarray in an aged immune system.

But of course, absent increasingly comprehensive medical support, the microbes will get you in the end. The cell and tissue damage of aging produces frailty throughout all of our biological systems, and it isn't just the immune system that becomes less resilient. The immune response becomes less able to defend against attackers, and at the same time it takes less of a disruption due to infection to produce a fatal decline in already precarious vital organ functions. A very great many old people are tipped over the edge by infections that they wouldn't have even noticed a few decades earlier in life. There is still a great deal of work to do in the control of infectious disease, a goal that will probably be more easily achieved by augmenting our natural immune systems with more efficient molecular nanotechnology than by sterilizing the world, but consider how rare fatal infections are nowadays for younger adults when compared to the old. The biggest gains in the near future will come through rejuvenation of the immune system: destroying and then recreating immune cells to remove misconfiguration; regenerating the thymus to increase the supply of new immune cells; supplying new pools of pristine bone marrow stem cells responsible for creating immune cells; and so on.

Classifying Aging As a Disease: The Role of Microbes

Recent publications have proposed that aging should be classified as a disease. The goal of this manuscript is not to dispute these claims, but rather to suggest that when classifying aging as a disease, it is important to include the contribution of microbes. As recently as ~115 years ago, more than half of all deaths were caused by infectious diseases. Since then, the establishment of public health departments that focused on improved sanitation and hygiene, and the introduction of antibiotics and vaccines allowed for a dramatic decrease in infectious disease-related mortality. In 2010, the death rate for infectious diseases was reduced to 3%. Simultaneously, as infectious disease-related mortality rates have decreased, global life expectancy has increased from ~30 to ~70 years.

Because death rates due to infectious diseases have been reduced to very low levels, we've forgotten about the adverse effects of microbes on our existence. The fact is, we live in a microbial world. Even at a young chronological age, microbes find their way into the blood and tissues. Circulating microbial DNA is found in young, healthy adults. Interestingly, levels of circulating bacterial DNA are not homogeneous: some subjects had 3-fold or more circulating bacterial DNA when compared with others. Moreover, various bacterial species are found in skeletal muscle, heart, liver, adipose tissue, and in the brains of young mice. With the passage of time, the barriers responsible for keeping microbes out of us weaken. For example, tight junctions (TJs) connect epithelial cells, thereby minimizing the space in between the cells, and minimizing the ability of microbes to translocate into the blood. Bacteria and viruses have evolved mechanisms to impair TJ assembly. Whether caused by pathogenic microbes or because of defects in host gene expression, levels of many of these tight junction proteins are decreased in old, when compared with young. Furthermore, although the immune system should protect us against an increase in microbial burden, however, many aspects of the immune response are decreased, whereas others are increased, thereby resulting in dysregulation. This phenotype is known as immunosenescence.

The impact of decreased barrier function and immunosenescence would be expected to lead to an increase in circulating microbes in old, when compared with young. Although circulating levels of bacterial DNA have yet to be reported in older adults, plasma levels of lipopolysaccharide (LPS), which is found in the outer membrane of gram-negative bacteria, and levels of the receptors that bind to LPS (TLR4) and to bacterial flagellin (TLR5), are elevated in older adults, when compared with young. In line with this, the incidence of bloodstream infections with LPS-containing Escherichia coli is increased by more than 10-fold in adults older than 74, when compared with subjects younger than 50 years. Similarly, the incidence of bloodstream infections with gram-positive bacteria is elevated by more than 8-17 fold in older adults.

What are the consequences of an age-related increase in microbial burden? Microbes and/or microbial products are causatively involved in multiple theories of aging, including insulin resistance, oxidative stress, inflammation, and telomere shortening. In support of this, LPS injection into young, healthy subjects causes insulin resistance. Oxidative stress is increased in response to the binding of LPS and bacterial flagellin to their respective receptors. Levels of the pro-inflammatory cytokines IL-6 and TNF-α are increased when LPS binds to TLR4. Telomere shortening occurs at a faster rate in the presence of cytomegalovirus (CMV) infection. Interestingly, the prevalence of CMV infection increases from ~20% in adults younger than 50 years, to ~40% in 50-70 year olds, to 100% in adults older than 70. Collectively, these data support a causative role for microbial burden on mechanisms that have been commonly hypothesized to drive the aging process. Microbial burden is also involved in mechanisms related to age-related disease, including cardiovascular disease (CVD), Alzheimer's disease, cancer, stroke, and diabetes. In support of this, approximately 10-fold more circulating bacterial DNA is found in CVD patients, when compared with healthy controls.

If we are fortunate to avoid the common age-related diseases and live to achieve centenarian status, infectious disease as a major cause of death arises again. In Japan, more than 40% of all centenarian deaths are due to infectious diseases, including pneumonia. Similarly, in a larger study of ~36,000 centenarians from the UK, other than "old age," the leading cause of death was pneumonia. In short, over the past 115+ years, we haven't eliminated the adverse effects of microbes on our health, we've merely delayed them! As an argument against the role of microbes on causing many aspects of aging and age-related disease, it is important to note that host aging does indeed occur in their absence. Although lifespan in microbe-free mice is increased by 20-50%, these animals are not immortal. Nonetheless, as presented here, microbes are involved in mechanisms related to aging and age-related disease, and accordingly, I posit that any classification of aging as a disease should include the contribution of microbes.