I first noted the gene engineering work on nematode worms that led to a tenfold extension of healthy lifespan late last year:

This and similar work forms an impressive set of technology demonstrations - there is no necessarily direct relevance to extending healthy human life span, but it certainly gets people fired up and excited.

Similar work that immediately springs to mind is the recent news of tenfold healthy life extension in yeast and 50% healthy life extension in mice, both also achieved through gene engineering.

More details on the nematode work (in the species C. elegans) are now available for those of us without a journal subscription at the UAMS website:

C. elegans are barely visible to the eye but are helping scientists unravel the causes of aging and understand what determines life span, Reis said. During the past 15 years, more than 80 mutations have been found that extend life in C. elegans, including components of a worm signaling pathway (a set of genes that responds to signals from the environment or within the worm) that is equally related to insulin signaling and insulin-like growth factor (IGF-1) signaling in mammals.

Insulin alerts cells that there are nutrients in the blood ready to be used, whereas IGF-1 stimulates growth. Interfering with insulin signaling results in insulin resistance, a condition that can develop into diabetes. Interfering with IGF-1 signaling produces effects in mammals more akin to those seen in long-lived worms. Mice mildly deficient in IGF-1 receptor are long-lived and appear healthy, Reis said, adding that the longest-lived humans tend to have diminished IGF-1 signaling as well.

“These observations hint that processes discovered in the worm also are relevant to aging in humans," Reis said, "but we shouldn’t expect exact parallels."

Reis' team discovered that a mutant in the insulin/ IGF-1 pathway of C. elegans slows development but ultimately produces adults he described as "super survivors," able to resist levels of toxic chemicals that would kill an ordinary worm. Although the adult lifespan of C. elegans is normally only two to three weeks, half of the mutant worms were still alive after six months, with some surviving to nine months.

"We knew we had found something amazing," said Srinivas Ayyadevara, Ph.D., research assistant professor in the UAMS Donald W. Reynolds Institute on Aging. "These worms continue to look and act like normal worms of one-tenth their age."

For those of you who like to dig deeper, a PDF of the scientific paper is freely available as well.

As I might have mentioned once or twice, chronic inflammation stretched over the years causes damage, suffering and death. It's a significant component of the processes of degeneration that accompany aging.

Inflammatory mechanisms: the molecular basis of inflammation and disease

Inflammation participates importantly in host defenses against infectious agents and injury, but it also contributes to the pathophysiology of many chronic diseases. Interactions of cells in the innate immune system, adaptive immune system, and inflammatory mediators orchestrate aspects of the acute and chronic inflammation that underlie diseases of many organs. A coordinated series of common effector mechanisms of inflammation contribute to tissue injury, oxidative stress, remodeling of the extracellular matrix, angiogenesis, and fibrosis in diverse target tissues.

Atherosclerosis provides an example of a chronic disease that involves inflammatory mechanisms. Recruitment of blood leukocytes characterizes the initiation of this disease. Its progression involves many inflammatory mediators, modulated by cells of both innate and adaptive immunity. The complications of established atheroma, including plaque disruption and thrombosis, also intimately involve inflammation.

Inflammatory biomarkers and risks of myocardial infarction, stroke, diabetes, and total mortality: implications for longevity

Inflammation is recognized as a major etiologic determinant of multiple disease states including myocardial infarction, stroke, diabetes, and metabolic syndrome, and individuals with elevated levels of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) are at increased risk of mortality and morbidity from these conditions.

So inflammation is not something you want too much of. But it does serve a purpose, as noted in this position paper.

Inflammation and the aging process: devil or angel

Inflammation is often viewed as a pathologic mechanism leading to tissue damage and interference with function, such as the process of chronic tissue scarring or fibrosis. However, it is important to note that inflammation is a crucial component of normal tissue repair as well as being fundamental to the body's defense against infection. Considering inflammation as a "causative agent in aging" belies the underlying mechanisms whereby the acute inflammatory response is necessary for survival, and efforts to reduce and control the inflammatory response leave the host susceptible to infectious agents and improper healing.

Chronic inflammation inevitably has initiating mechanisms that include immune, autoimmune, and metabolic pathways, leading to the activation and presence of the host-protective response. It is more appropriate to target the underlying initiating conditions than the inflammatory process that ensues and treat the basic mechanisms of disease rather than interfere in a very important protective mechanism of the host.

Which is a good point, and very SENS-like thinking. Follow the biochemical chain of age-related changes until you find the largest lever you can move with the biotechnology of today or tomorrow, and thus shut down all the undesirable changes downstream from that lever. What are these underlying conditions that lead to runaway inflammation?

Inflammaging as a major characteristic of old people: can it be prevented or cured?

Inflammation is necessary to cope with damaging agents and is crucial for survival, particularly to cope with acute inflammation during our reproductive years. But chronic exposure to a variety of antigens, especially to some viruses such as cytomegalovirus, for a period much longer than that predicted by evolution, induces a chronic low-grade inflammatory status that contributes to age-associated morbidity and mortality. This condition carries the proposed name "inflammaging". Centenarians are unique in that, despite high levels of pro-inflammatory markers, they also exhibit anti-inflammatory markers that may delay disease onset. The key to successful aging and longevity is to decrease chronic inflammation without compromising an acute response when exposed to pathogens.

So one might view an increase of chronic inflammation with age as a slow failure of the immune system under accumulated load, operating far past its point of evolutionary optimization. It is promising that cytomegalovirus - and very similar viruses - contribute so greatly to this failure, given that inroads are already being made into dealing with this root cause of immune system aging:

• Fighting Cytomegalovirus
• Rebooting the Immune System