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The Small Molecule View: Searching for Drugs to Slow Aging

Today I thought I'd point out a couple of interesting papers on the work of finding drugs to intervene in the aging process. This is far from a widespread undertaking, even now that more funding is arriving into the field. The majority of researchers focused on aging are not looking to intervene in the aging process at all, and their work is purely investigative. Equally, the majority of research into age-related disease is focused on working backwards from the disarray of a diseased metabolism, tracing molecular links in long chains of cause and effect that hopefully lead closer to causes rather than dead ends. At each new discovery, some groups stop to develop therapies, screening for drugs that can influence the newly uncovered link in a beneficial way, while causing few enough side-effects to be acceptable. Preference is typically given to existing drugs, even if they are much less effective than a theoretical new drug, because it is less expensive to push that through the regulatory system. The nature of this approach means that the resulting therapies largely involve tinkering with an already complex, failed metabolic state, without addressing the root causes of that failure, and are therefore only marginally effective. This is the story of most medical research: expensive drug development, massive regulatory costs, perverse incentives to create less effective treatments, and tiny gains at the end of the day.

There is a completely different approach to the problem of age-related disease, however, which is to start from the beginning and the known root causes of aging, and try to repair and revert these causes prior to a full understanding of the chain of cause and effect that drives the progression of aging. Don't try to work forward to full understanding of the process, just fix things where there is compelling evidence for their involvement in aging and see what happens. This should be much less challenging than the mainstream approach of working backwards from the disease state, and should produce far better results. It should also answer many questions as to the root causes of specific age-related diseases, and far more efficiently than working backwards through the complexity of late stage disease. How do researchers know what the root causes of aging are with such great reliability? Over the years, many, many research groups have compared old tissue and young tissue, and ruled out everything that has a direct cause other than the operation of normal metabolic processes. What is left is a consensus list of side-effects and molecular damage, the fundamental changes that are produced in the cells of normal, healthy, young individuals, and that slowly turn them into aged, diseased, and ultimately dead individuals. Unfortunately this better approach of repair has yet to gain more than a foothold in the research community. There is a long way to go yet before we can call rejuvenation research a mainstream, well-funded concern.

If you look through the SENS rejuvenation research programs, it is clear that there is a role for traditional or more modern drug discovery and development in a number of areas. There may prove to be good enough drug-based approaches to senescent cell clearance, for example, to compete in the marketplace with the more efficient and directed gene therapy techniques pioneered by Oisin Biotechnologies. Work on breaking down glucosepane cross-links will also no doubt settle down to some form of drug development once an initial class of compounds shows effectiveness. There are other examples, such as the work of Pentraxin Therapeutics or Human Rejuvenation Technologies that are both fairly standard issue drug development and relevant to the SENS vision. So all in all, I think you'll find the open access papers below interesting, even if they have little to say in and of themselves on the topic of rejuvenation research, being more focused on methods of altering metabolism to slightly slow aging.

Finding Ponce de Leon's Pill: Challenges in Screening for Anti-Aging Molecules

Several drugs have demonstrated great promise in the laboratory setting in enhancing the healthspan and lifespan of multiple species, including mice, raising the possibility that efficacious pharmacologic anti-aging therapy in people may be possible. However, screening for novel small molecules with anti-aging effects in mammals in an unbiased fashion represents an enormous, potentially insurmountable challenge. Alternatively, since it is clear that several cellular pathways affect longevity in an evolutionarily conserved manner, invertebrate models may be quite useful for such screening endeavors. However, some known molecular factors with major effects on mammalian lifespan are not well conserved between invertebrates and mammals. Consequently, small molecule screening efforts relying exclusively on the use of invertebrates will likely miss drugs with potent effects on mammalian aging. Moreover, many of the key physiologic features of humans and other mammals are not well modeled in invertebrates, as the latter lack specific tissues like heart and kidney and complex endocrine, nervous, and circulatory systems that are crucial targets of mammalian aging and age-related pathologies. Most invertebrate aging models possess limited regenerative capabilities and incompletely recapitulate processes such as stem cell renewal, which are required for tissue repair mechanisms that maintain tissue homeostasis in mammals, in order to sustain organ function over years and decades.

To date, the discovery of anti-aging compounds has so far been carried out via two basic approaches. One of these is phenotypic, defined as the screening of compounds in cellular or animal models to identify drugs conferring desired biological effects, i.e. lifespan extension. Although this approach has proven enormously valuable in many areas of biochemical research, identifying drugs that can modulate lifespan is more time consuming, complex, and expensive than for many other phenotypes. Moreover, elucidating the mechanism of action of agents identified in such phenotypic, "black box" screens represents a formidable challenge, though the powerful genetic tools available in invertebrate models can facilitate such efforts. A complementary approach involves target-based screening for modulators of pathways known or strongly suspected to modulate the aging rate. However, by definition, such efforts are unlikely to identify novel cellular factors and pathways involved in longevity.

A related challenge in aging research at present is the lack of primate model systems with reasonably short lifespan for preclinical testing of candidate anti-aging drugs. The most commonly used model, the rhesus monkey, lives for three to four decades. In Europe, the marmoset is used as a non-rodent species for drug safety assessment and toxicology. However, their maximal lifespan is ~17 years - shorter than the rhesus monkey, but still highly impractical for testing pharmacological interventions aimed at extending longevity. The development of new mammalian aging models besides the mouse would be extremely helpful to better elucidate the biological processes underlying mammalian aging and to expedite the translation of pharmacological interventions from the laboratory to actual clinical use in humans. One model to consider in this regard is dogs, which share their social environment with humans. Furthermore, dogs are relatively well understood with regard to aging and disease, exhibit great heterogeneity in body size and lifespan, and provide a large pool of genetic diversity. Testing candidate anti-aging compounds in humans represents an enormous challenge. It is highly unlikely that pharmaceutical companies can be persuaded to engage in decades-long clinical trials of candidate anti-aging medicines with lifespan as an endpoint. The evaluation of shorter-term surrogate phenotypes, such as molecular markers or age-associated defects such as impaired responses to vaccination, may permit initial clinical evaluation of candidate anti-aging compounds in a more reasonable timeframe.

Biology of Healthy Aging and Longevity

As a heterogeneous process, aging may occur at different rates across diverse organisms, and even organisms of the same species can age at variable rates. At the biological level, aging is characterized by the accumulation of molecular and cellular damage, which leads to structural and functional aberrancies in cells and tissues, such as loss of mitochondrial homeostasis, impaired intercellular communication, senescence (cell arrest that hampers growth and division), and decreased regenerative capacity. The ability of organisms to overcome stress and respond to external environmental challenges/insults is blunted within aged individuals when compared to younger counterparts. Healthy aging, however, refers to the warding off of molecular and cellular decline for the longest length of the lifespan. Not surprisingly, healthy aging has been associated with increased longevity. This claim is substantiated by the fact that genetic, dietary, and/or pharmacological interventions that promote cellular homoeostasis, stress resistance, and protection against age-related diseases also tend to extend lifespan and vice versa.

Overwhelming scientific evidence supports the claim that there is no single cause of aging. Indeed, notable advancements in the biology of aging, especially during the last few decades, have contributed to the identification of multiple mechanisms that modulate the aging process. Despite this progress, uncovering interventions that can achieve healthy aging in humans is challenging. The conserved molecular and cellular mechanisms that underlie aging, especially how these pathways interplay and how complex lifestyles and environments to which humans are exposed modify them, are not completely understood.

Despite the impressive advancements made towards understanding more about the molecular basis of aging, there is still no definitive intervention for ensuring healthy aging in humans. To uncover new therapeutic avenues, we need to gain deeper knowledge about how different internal and external factors regulate the cellular hallmarks of aging, and how their regulation changes across time and individuals. All molecular pathways exhibit complex communication known as "crosstalk." The genome, epigenome, organelles, proteome, and pathways such as those involving sirtuins, mTOR, AMPK, and insulin/insulin-like growth factor-1 signaling - all integrate and process signals that must act coordinately to promote homeostasis in cells and tissues. It is unclear, however, how these complex molecular networks are affected by diverse environmental challenges and how they become impaired with aging. Lastly, in an effort to find beneficial interventions to delay aging-linked deterioration, the search for small molecules that can mimic calorie restriction - and the dissection of their pharmacological modes of action in vivo - is a growing area of research that merits more attention. Collectively, through all of these scientific efforts, we may someday achieve the longstanding human dream of living a long and healthy life.

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