Therapeutic Manipulation of Ageing: Repurposing Old Dogs and Discovering New Tricks

Mallikarjun, Venkatesh; Swift, Joe

doi:10.1016/j.ebiom.2016.11.020

Cited by 15 publications

(17 citation statements)

References 78 publications

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“…Pharmacological Targeting of Aging As with most diseases, traditional pharmacological approaches are the most straightforward and widely explored way to target aging. This topic has been reviewed [1,4,11,12] and therefore is only briefly discussed here (Box 1). 202 deaths per annum from an average yearly population size of 315 109 368 were recorded (0.818%).…”

Section: Anti-aging Biotech Companies and Approachesmentioning

confidence: 99%

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The Business of Anti-Aging Science

Magalhães

Stevens

Thornton

2017

Trends in Biotechnology

132

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Age-related conditions are the leading causes of death and health-care costs. Reducing the rate of aging would have enormous medical and financial benefits. Myriad genes and pathways are known to regulate aging in model organisms, fostering a new crop of anti-aging companies. Approaches range from drug discovery efforts to big-data methods and direct-to-consumer (DTC) strategies. Challenges and pitfalls of commercialization include reliance on findings from short-lived model organisms, poor biological understanding of aging, and hurdles in performing clinical trials for aging. A large number of potential aging-associated interventions and targets exist, but given the long validation times only a small fraction can be explored for clinical applications. If even one company succeeds, however, the impact will be huge.

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Section: Anti-aging Biotech Companies and Approachesmentioning

confidence: 99%

“…Other companies are using big-data techniques to find new uses for already approved drugs [12]. This is an attractive approach as pharmaceutical companies incur US$1.8 billion in capitalized costs to develop and obtain approval for drugs from scratch, while the safety of approved drugs is already known [33].…”

Section: Basic Biology and Big Datamentioning

confidence: 99%

The Business of Anti-Aging Science

Magalhães

Stevens

Thornton

2017

Trends in Biotechnology

132

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“…As the population continues to age it is important to understand how hormone deficiency interacts with chronological ageing to alter structural and mechanical features of tissues. This in turn should highlight opportunities for therapeutic intervention, such as by targeting pathways of mechano-signalling, or by directly modifying the tissue mechanical properties (Mallikarjun and Swift 2016).…”

Section: Resultsmentioning

confidence: 99%

Distinct matrix composition and mechanics in aged and estrogen-deficient mouse skin

Saville¹,

Mallikarjun²,

Holmes³

et al. 2019

Preprint

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Hormone deficiency has been widely linked to accelerated tissue ageing, and increased incidence of chronic degenerative disease. Furthermore, age-associated hormonal dysregulation is thought to be a major contributing factor to the increased fragility of aged skin. The ageing process is driven by an aggregation of damage to cells and extracellular matrix, which can directly influence the mechanical properties of the tissue. Here we report on the correlation between mechanical properties and composition of skin from ovariectomised and aged mice, to assess the extent to which estrogen deprivation drives dermal ageing. We found that age and estrogen abrogation affected skin mechanical properties in contrasting ways: ageing led to increased tensile strength and stiffness while estrogen deprivation had the opposite effect. Mass spectrometry proteomics showed that the quantity of extractable fibrillar collagen-I decreased with ageing, but no change was observed in ovariectomised mice. This observation, in combination with measurements of tensile strength, was interpreted to reflect changes to the extent of extracellular matrix crosslinking, supported by a significant increase in the staining of advanced glycation endpoints in aged skin. Loss of mechanical strength in the skin following ovariectomy was consistent with a loss of elastic fibres. Other changes in extracellular matrix composition broadly correlated between aged and ovariectomised mice, confirming the important role of estrogen-related pathways in ageing. This study offers new insight into the relationship between tissue composition and mechanics, and suggests that the deleterious effects of intrinsic skin ageing are compounded by factors beyond hormonal dysregulation.

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“…The skin also contains all the enzymes required to synthesise steroid hormones from cholesterol and this provides a major source of estrone in postmenopausal skin [74]. Indeed, a more detailed understanding of estrogen's dramatic effects on the elastic fibre system is essential to develop new pharmacological interventions to extracellular matrix maintenance and age-associated pathologies [75]. Such treatments may be based on the manipulation of ER signalling, as have previously been achieved of ERb selective agonist effects on wound repair [52,58,76].…”

Section: Discussionmentioning

confidence: 99%

Estrogen mediates acute elastic fibre homeostasis in skin

Saville

Holmes

Swift

et al. 2019

Preprint

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Remodelling of the dermal extracellular matrix makes a major contribution to skin fragility in the elderly.The peri-menopausal period in females is also associated with an age-like phenotype which can be reversed by hormone replacement therapy. This suggests a direct link between circulating hormone levels and tissue ageing. Despite work investigating the role of estrogen as a regulator of collagen fibril abundance and structure, the influence of estrogen on the elastic fibre system remains poorly defined.Here we used an ovariectomised (Ovx) mouse surgical menopause model to show that just 7 weeks of acute hormone deficiency significantly decreased skin tensile strength and elasticity. Systemic replacement of 17β-estradiol to physiological levels protected against these changes to the skin mechanical properties. Moreover, acute hormone deficiency differentially influenced dermal structural networks, significantly decreasing dermal elastic fibre abundance without discernible effect on collagen fibril organisation or abundance. We suggest that this specific elastic fibre proteolysis may be driven by extracellular protease activity, or be a consequence of significant adipocyte hypertrophy.17β-estradiol supplementation in Ovx mice in vivo protected the elastic fibre system. Treatment of human dermal fibroblasts with 17β-estradiol in vitro induced the selective upregulation of tropoelastin, fibrillin-1 and associated elastic fibre-associated proteins (including EMILINs and fibulins). In summary, these data show that the elastic fibre system is significantly perturbed by estrogen deprivation. Thus, pharmacological intervention may slow the acute effects of menopause and potentially the chronic effects of ageing in skin.

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Therapeutic Manipulation of Ageing: Repurposing Old Dogs and Discovering New Tricks

Cited by 15 publications

References 78 publications

The Business of Anti-Aging Science

The Business of Anti-Aging Science

Distinct matrix composition and mechanics in aged and estrogen-deficient mouse skin

Estrogen mediates acute elastic fibre homeostasis in skin

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