Pharmacological Targeting of Aging

1 de Magalhaes J.P.

et al. Genome–environment interactions that modulate aging: powerful targets for drug discovery. 4 Kennedy B.K.

Pennypacker J.K. Drugs that modulate aging: the promising yet difficult path ahead. 11 Vaiserman A.M.

et al. Anti-aging pharmacology: promises and pitfalls. 12 Mallikarjun V.

Swift J. Therapeutic manipulation of ageing: repurposing old dogs and discovering new tricks. Box 1 A Plethora of Potential Drug Targets 1 de Magalhaes J.P.

et al. Genome–environment interactions that modulate aging: powerful targets for drug discovery. 2 Tacutu R.

et al. Human Ageing Genomic Resources: integrated databases and tools for the biology and genetics of ageing. 6 Fernandes M.

et al. Systematic analysis of the gerontome reveals links between aging and age-related diseases. 62 Smith E.D.

et al. Quantitative evidence for conserved longevity pathways between divergent eukaryotic species. 3 Kenyon C.J. The genetics of ageing. 1 de Magalhaes J.P.

et al. Genome–environment interactions that modulate aging: powerful targets for drug discovery. The multitude of genes, processes, and pathways modulating aging in short-lived model organisms provide a plethora of potential targets for drug discovery []. Hundreds of genes modulating aging and/or longevity have been identified in model organisms [], most of which can be grouped into common pathways and processes like insulin/insulin-like signaling, autophagy, oxidative phosphorylation, and TOR signaling []. There is also evidence that life-extending pathways tend to be evolutionarily conserved []. For instance, disruption of the insulin–IGF1 pathway has been shown to extend lifespan in yeast, worms, flies, and mice and IGF1R mutations have been associated with human longevity []. Thus, evolutionarily conserved life-extending genes and pathways are important targets for drug discovery []. As with most diseases, traditional pharmacological approaches are the most straightforward and widely explored way to target aging. This topic has been reviewed [] and therefore is only briefly discussed here ( Box 1 ).

1 de Magalhaes J.P.

et al. Genome–environment interactions that modulate aging: powerful targets for drug discovery. 1 de Magalhaes J.P.

et al. Genome–environment interactions that modulate aging: powerful targets for drug discovery. 13 Harrison D.E.

et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. 14 Mannick J.B.

et al. mTOR inhibition improves immune function in the elderly. Notable examples of anti-aging drug discovery efforts include pharmacological manipulations of sirtuins, sirtuin 1 (SIRT1) in particular (targeted by resveratrol), and TOR (targeted by rapamycin), which are currently being explored []. TOR inhibition by rapamycin results in increased lifespan from yeast to mammals []. In a small but groundbreaking clinical trial by Novartis, rapamycin improved immune function in elderly volunteers []. Because rapamycin has various side effects, companies and laboratories are trying to develop safer analogs, known as ‘rapalogs’. One company focusing on the TOR pathway is Navitor Pharmaceuticals, which aims to treat diseases of aging through selective regulation of the mTOR pathway. Another similar company focused on rapalogs, Mount Tam Biotechnologies, has worldwide licensing rights to the Buck Institute’s research assets related to autoimmune disease including the rapalog TAM-01 ( http://www.buckinstitute.org/buck-news/buck-mt-tam-biosciences-target-lupus ).

1 de Magalhaes J.P.

et al. Genome–environment interactions that modulate aging: powerful targets for drug discovery. 15 Miller R.A.

et al. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. 16 Schmidt C. GSK/Sirtris compounds dogged by assay artifacts. 17 Hubbard B.P.

Sinclair D.A. Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Research on resveratrol and sirtuins was high profile in 2008 when GlaxoSmithKline (GSK) purchased the sirtuin-focused biotech company Sirtris (based on work at Harvard Medical School) for US$720 million. Enthusiasm for resveratrol and sirtuins as anti-aging compounds has arguably declined in more recent years. Briefly, results have been largely disappointing since then [], with resveratrol failing to extend lifespan in studies in mice [] among other controversies []. GSK has closed Sirtris, although research on sirtuins and on new chemical entities that are thought to active sirtuins [] is still reportedly ongoing at GSK ( http://blogs.nature.com/news/2013/03/gsk-absorbs-controversial-longevity-company.html ). While Sirtris demonstrated that anti-aging biotech companies could rapidly grow in value and become a financial success for founders and early investors, its more recent problems might have hurt subsequent anti-aging science-based enterprises by discouraging investors and entrepreneurs.

8 de Magalhaes J.P. The biology of ageing: a primer. 18 de Magalhaes J.P.

Church G.M. Cells discover fire: employing reactive oxygen species in development and consequences for aging. 19 Lapointe J.

Hekimi S. When a theory of aging ages badly. 20 Bjelakovic G.

et al. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Antioxidants have been historically a major focus of the field. However, currently the idea that antioxidant pathways play a major role in aging is being challenged [], and epidemiological studies have largely failed to support the supposed benefits of antioxidants []. While many dietary supplements still focus on antioxidants, few companies in the field maintain such a focus. One exception is Antoxis, founded in 2005, which designs and synthesizes therapeutic antioxidants.

8 de Magalhaes J.P. The biology of ageing: a primer. 21 de Magalhaes J.P. How ageing processes influence cancer. 8 de Magalhaes J.P. The biology of ageing: a primer. 21 de Magalhaes J.P. How ageing processes influence cancer. 22 de Magalhaes J.P.

Toussaint O. Telomeres and telomerase: a modern fountain of youth?. 23 Bernardes de Jesus B.

et al. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. 24 Bär C.

Blasco M.A. Telomeres and telomerase as therapeutic targets to prevent and treat age-related diseases. 25 Hamzelou J. Time to stop getting old. Telomeres, the protein-bound structures at the ends of chromosomes, shorten with cell division and, at least in some tissues, with age []. Although genetic manipulations of telomerase in mice have yielded conflicting results [], one study found that overexpression of telomerase in adult mice led to a 24% increase in median lifespan while not increasing the incidence of cancer []. Therefore, the idea of activating telomerase as anti-aging remains a powerful one, even resulting in one self-experiment using gene therapy by BioViva []. One notable company working on telomerase activation, Sierra Science, claims to have screened 250 000 compounds. Other companies focus on particular age-related diseases, such as Telocyte, which is working on telomerase activation for Alzheimer’s disease.

8 de Magalhaes J.P. The biology of ageing: a primer. 26 de Magalhaes J.P. From cells to ageing: a review of models and mechanisms of cellular senescence and their impact on human ageing. Ink4a-positive cells (a marker of senescence) once per week from age 1 year extended the median lifespan in two normal strains of mice by 24–27%, although maximum lifespan was (slightly) increased in only one strain. Tumorigenesis and age-related deterioration of heart and kidney were delayed or slowed [ 27 Baker D.J.

et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. 28 Wang Y.

et al. Discovery of piperlongumine as a potential novel lead for the development of senolytic agents. 29 Squires, S.C. Cenexys, Inc. Compositions and methods for detecting or eliminating senescent cells to diagnose or treat disease, US20150151001. Telomere shortening, as well as various stressors, can cause proliferating cells to stop dividing and enter a proinflammatory senescent state. There is evidence that senescent cells accumulate with age, at least in some tissues []. In a landmark study, drug-induced clearance of p16-positive cells (a marker of senescence) once per week from age 1 year extended the median lifespan in two normal strains of mice by 24–27%, although maximum lifespan was (slightly) increased in only one strain. Tumorigenesis and age-related deterioration of heart and kidney were delayed or slowed []. As a consequence, Unity Biotechnology, a company founded by researchers at the Mayo Clinic involved in the abovementioned work as well as the Buck Institute, has raised US$116 million from investors including Amazon founder Jeff Bezos to develop senolytic (i.e., an agent that destroys senescent cells) treatments. Continuing research by the cofounders has focused on senolytic agents, including the killing of senescent fibroblasts with piperlongumine and ABT-263 []. Interestingly, they have also acquired a patent related to a senescent cell antibody for imaging and delivery of therapeutic agents [].

Ink4a expression may be a subclass of macrophage termed senescent associated macrophages (SAMs) [ 30 Hall B.M.

et al. Aging of mice is associated with p16Ink4a- and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells. Other companies focusing on senolytics include Oisin Biotechnologies, although, according to their website, they seem to be developing a genetically targeted intervention to clear senescent cells, suggesting a different approach than Unity. Moreover, Everon Biosciences has shown that a significant portion of cells with p16expression may be a subclass of macrophage termed senescent associated macrophages (SAMs) []. Following this discovery Everon has announced that they will focus on these SAMolytic agents. Last, Siwa Therapeutics’ focuses on developing antibodies against senescent cell markers capable of identifying and removing senescent cells.