Aging is a universal problem which can be associated with multiple disorders. Frequently age is considered a risk factor for these disorders, but what if it is the cause? And if that is the case, could preventing aging also prevent these disorders from arising? The lab of Dr. Gordon Lithgow is focused on determining pharmacological interventions that can work to delay or prevent aging altogether. These interventions can be synthetic and lab-made, natural products, or can be metabolites already found in the human system.

Pharmacologyprism

Pharmocological interventions can potentially alter the performance of many bodily functions to enhance health and lifespan. Image from Wikimedia Commons.

Model Systems

Often the search for age-delaying compounds incorporates a pharmacological screen in which numerous compounds are tested for efficacy. In vitro (cell culture) screens are useful because they provide fast results and allow for analysis on focused targets. On the other hand, in vivo screens in living models such as roundworms (C. elegans), flies (D. melanogaster), and mice (M. musculus) allow for full lifespan analyses and an understanding of how a compound affects a complex system. Even within the in vivo models there is much to consider.

Worms are useful because they are small and easy to maintain, and they have a short lifespan which allows for quick analysis. They are, however, evolutionarily distant from humans, thus results found in worms may not necessarily translate to humans.

Flies are useful due to many genetic technologies available, which allow for intensive genetic investigations. They are also useful for population studies and observing complex behaviors.

Mice are very relevant to human studies due to their evolutionary similarities, but they also are very expensive to maintain and live much longer than simpler models, which means aging studies can take a long time.

The Challenge of Reproducibility

Even with a reliable model, there are significant challenges to verifying a finding. Perhaps the greatest of these is reproducibility. It is not uncommon for one lab to discover a connection between a compound and lifespan extension in a model system, only for another lab to challenge this finding. One example, superoxide dismutase was shown to extend lifespan in 2000, only for opposing results to be published in 2003. These differing results could be attributed to a number of things, such as variations in media ingredients, lab conditions, or even the genetics of the models being used. In the attempt to find more consistent results, the National Institute of Aging (NIA), one of 27 agencies within the National Institutes of Health (NIH), developed the Interventions Testing Program , which focuses on standardizing procedures at multiple testing sites. Despite these efforts, inconsistencies in methods and results remain common. One intervention that has shown promise is rapamycin, which in multiple experiments has been shown to slow aging in model organisms, such as two notable studies in mice in 2009 and 2012. Difficulties with reliable results are a pressing issue with pharmacological research, but are a necessary problem to overcome.

Promising Therapies Identified

Insoluble proteins accumulate with age and may contribute to the onset of deadly age-related diseases. This Western blot shows the accumulation of insoluble proteins in aged worms (right-most lane).

Insoluble proteins accumulate with age and may contribute to the onset of deadly age-related diseases. This Western blot shows the accumulation of insoluble proteins in aged worms (right-most lane). (Aging Cell)

Despite these controversies facing intervention research, there have been many useful findings. The Lithgow lab has placed a large focus on investigating protein homeostasis as a target of aging. Multiple age-related diseases such as Alzheimer’s and Parkinson’s are associated with the accumulation of protein aggregates. If it is possible to prevent this aggregation, could this also prevent or delay the onset of some deadly age-related diseases? Results have shown that intervention with Thioflavin T, an amyloid-binding dye, can reduce the toxic effects of Alzheimer’s associated β-amyloid plaques and extends lifespan in worms. Furthermore, compounds such as curcumin, rifampicin, and 2–(2–hydroxyphenyl benzoxazole (HBX) also have been able to improve the lifespan of worms. Through proteomic screening of age-dependent changes in protein solubility, the Lithgow lab in collaboration with other labs at the Buck identified specific genes associated with lifespan modulation). Now, it is hypothetically possible to regulate these genes to prevent age-related protein aggregation. Dr. Lithgow’s lab has since focused on identifying ways to decrease the levels of insoluble proteins that accumulate with age (the “insolublome”). Two important findings are (1) lithium can reduce the insolublome and (2) iron can promote it in worms. These findings suggest the value of performing future tests in vertebrate models that are more similar to humans.

The continuing search for pharmacological compounds that can extend lifespan has provided promising results. One significant challenge to this search, as mentioned, is reproducibility between labs. Efforts are underway to reduce lab-to-lab disparities. The work of many labs, including the Lithgow lab, has shown that a number of compounds have positive effects in simple models. The expectation is that some set of these compounds will have similar effects on more complex models such as mice, and one day will be effective in extending the life and health of humans.