Fight Aging!

Compression of morbidity is a reduction in the length of time spent in significant illness or disability at the end of life. It is often touted as a goal in human medicine by those who, for various reasons, don't want to talk about the prospects for extending overall life span through progress in medicine. If we think about aging in terms of damage to a machine, then in the simple model of a single form of damage, compression of morbidity would not be expected to occur in response to a slowed accumulation of damage. Fully functional life span would extend, but so would the period of progressive onset of dysfunction.

Humans are machines, albeit very complicated machines. There is some debate over whether compression of morbidity in humans is possible to achieve, or happening at present as a result of improvements in public health and medical technology, in the context of overall life expectancy slowly increasing year over year. This is one of many areas of epidemiology in which data can be assembled to support almost any view of the situation, while definitions and what is actually being measured make a big difference, particularly the specifics of what is meant by "morbidity" in late life.

The roots of aging consist of a number of different forms of molecular damage. They do interact with one another, and tend to make one another worse, accumulating more rapidly as damage grows, but is possible to envisage a situation in which some forms of damage (a) are less influenced than others by public health measures or medical technology, and (b) only produce very significant mortality very late in life. This may or may not in fact be the case, but the accumulation of transthyretin amyloid in the cardiovascular system with age is a possible candidate. It does appear to influence mortality in younger old age, but there is evidence for it to be the majority cause of death in supercentenarians. In this scenario, therapies to treat aging that failed to change the burden of transthyretin amyloid would tend to produce compression of morbidity.

In today's open access paper, researchers note an absence of compression of morbidity in nematode worms subject to longevity-inducing mutations. This change in metabolism lengthens the period of healthy life span but also lengthens the period of disability in proportion - which is akin to the simple model of a damaged mechanism mentioned above. This work is also an example of the importance of details when it comes to the assessment of morbidity; the paper is in a part a discussion of a novel means for determining whether an old nematode is in fact decrepit, with the implication that earlier studies were not assessing degeneration well enough or in a relevant way.

Longevity interventions temporally scale healthspan in Caenorhabditis elegans

The continuously growing elderly population is projected to result in 1.5 billion people older than 65 years globally by 2050. This poses a significant challenge, as old age is the major risk factor for developing cancer, dementia, cardiovascular, and metabolic diseases, especially because people suffer for approximately 20% of their lifespan from one or multiple of these chronic illnesses, which are themselves accompanied by other late-life disabilities. Current estimates indicate that delaying the onset of these chronic diseases by one year would save $38 trillion in the US alone. Therefore, major research efforts are dedicated to understanding how to increase the time spent in good health (i.e., healthspan) and to postpone and compress the time spent suffering from age-related pathologies and chronic diseases (i.e., sickspan).

Mutations in genes that promote longevity in model organisms, such as Caenorhabditis elegans, have been instrumental in identifying mechanisms that promote healthy aging. A recent study has questioned this approach of using C. elegans longevity mutants to gain insights for promoting healthy aging or mechanisms that prolong healthspan. Using four matrices (resilience to heat and oxidative stress, voluntary movement, and swimming performance) to assess the "health" status of aging C. elegans, they found that four commonly used longevity mutants outperformed wild type at any given time point at older ages, consistent with previous reports. However, compared with their maximum lifespan, longevity mutants displayed an increased sickspan-to-healthspan ratio compared with wild type. Other studies have not observed an increase of sickspan in long-lived C. elegans mutants, except in the case of lower mobility or movement scores for the insulin/IGF-1 receptor longevity daf-2 mutants.

Although all these studies showed that sickspan is not increased in longevity mutants, the question remained about how healthspan changes when the lifespan is extended. We hypothesized that using other health matrices independent of voluntary or behavioral influences, such as physical properties of muscular strength, which is one of the best predictors for all-cause mortality in humans, we might be able to quantify the health trajectory of C. elegans longevity mutants.

Here we confirm that voluntary movement during aging declines, and this fragility is not extended in longevity mutants, except mildly in daf-2 mutants, using high-resolution lifespan and movement measurements on plates. We developed a novel microfluidic device and applied acoustophoretic force fields to quantify the maximum force and power of C. elegans. Using a high-frequency and high-power acoustic force field, it becomes possible to set up a contactless, constant in time, and uniform force field acting along the whole C. elegans body. Therefore, this force field challenges swimming C. elegans in a similar way body-weight exercises do for humans in a gravity field. Furthermore, applying the acoustic field stimulated a swimming response of resting C. elegans. All longevity mutants showed delayed onset of the decline in maximum force and dynamic power during aging. We observed heterogeneity between individuals across all genotypes in the onset of age-related phenotypes, several correlated phenotypes, and a time-dependent occurrence of multiple disabilities. However, we did not find a compression of sickspan but rather a temporal scaling of healthspan relative to their maximal lifespan across genotypes.