Affordable Preventive Healthcare: United Nations' SDG "Good Health and Well-Being" Knowledge Series - Part 4

Author:

Kenneth Kwok, Founder and CEO, Global Citizen Capital, and Co-President, AWAWA

This Knowledge Series is dedicated to my mother Ms. Evanda Li, my father Mr. Lawrence Kwok and to my late uncle Mr. KB Wong, who inspire me to become a better man every day, for myself, family, friends, community and world.

Overview of the Knowledge Series

To understand preventive healthcare, we have to first understand more about aging, which is the natural event occurring in all living organisms and can be defined as a deterioration of the cell functioning due to damage accumulation over time. This is an important biological, demographic and socio-economic issue all over the world. All living organisms have different longevity, indicating that evolution has played an important role in regulation and flexibilization of aging between species, in a relatively fast process. The understanding of the molecular basis of aging and longevity could let us manipulate it somehow in the future. In this regard, in the last 50 years numerous investigations related to aging have emerged, trying to explain this unstoppable process.

On this basis, preventive healthcare deals with the prevention of illness to decrease the burden of disease and associated risk factors. Preventive measures can be applied at all stages across the lifespan and along a disease spectrum, to prevent further decline over time. This 10 part series highlights the various key factors associated with aging and recommends examples of preventive recommendations, with a focus on affordability and access. Afterall, United Nations’ Sustainable Development Goal Number 3 – Good Health and Well-Being – targets ensuring healthy lives and promoting well-being for all at all ages.

Global Citizen Capital, in association with AWAWA, is honoured to participate in and contribute towards the combined UNDP, WHO and SDG initiatives to promote the conceptualization and commercialization of affordable preventive healthcare.

Knowledge Series - Part 4 – Loss of Proteostasis

Introduction

In our cells, proteins are produced constantly, and they control almost every function inside the cell. They move materials, carry signals, turn processes on and off, and provide structural support for the cell. The cellular pathways involved in maintaining the integrity of the proteome are collectively referred to as the proteostasis network. This network coordinates protein synthesis, folding, localization, modification, assembly, and turnover.

Proteins have to be recycled regularly because they lose their effectiveness over time. As we age, our bodies lose the ability to eliminate old proteins. 

If our bodies can't turn over unusable proteins, they can build up and become toxic. Protein accumulation is one of the major features of Alzheimer's disease — proteins called beta-amyloid aggregate in the brain and result in the loss of nerve cells. 

History of Research

Proteostasis is one of the major functions of autophagy in normal tissues. Imbalance of proteostasis due to aging leads to protein aggregation, accumulation of misfolded proteins and in the end to cellular dysfunction, among others (1). Notably, carbonylation due to oxidative stress is one of the changes that leads to loss of proteostasis (2). To avoid cell death or dysfunction, numerous homeostatic mechanisms turn on, mainly autophagy (3) and the Ubiquitin-Proteasome-System (UPS). Because autophagy is considered one of the most important intracellular homeostatic processes, an alteration or deterioration of this pathway could modify the normal cell functioning, including a variety of diseases and normal cell physiology declination. Autophagosomes and lysosomes decline in an age-dependent manner in muscles, heart, and several other tissues. Moreover, CMA has also been implicated in removing oxidized and potentially dangerous proteins by direct lysosomal degradation (4).

The UPS is mostly implicated in the degradation of misfolded proteins, as well as short- and long-lived proteins by their ubiquitination. This process is achieved thanks to three major proteins that sequentially activate the ubiquitin tag (E1), transfer it to a second enzyme (E2), and finally ligate the ubiquitin tag to the target molecule (by E3 ligase), which eventually reaches the proteasome for degradation (5). It is important to note that almost all regulatory proteins are substrates for this system (6), and UPS declines with age. Interestingly, mTORC1 was found to regulate not only lysosomal protein degradation, but also proteasomal proteolysis of long-lived proteins, independently of protein synthesis, suggesting a common regulation of both proteolytic systems by nutrient-sensing.

In addition, overexpression of a sole subunit of the proteasome enhanced its activity and the survival against several oxidants in two cell lines as well as primary culture of human fibroblasts (7). Moreover, proteasome activity decreased in an age-dependent manner (8). Overexpression of proteasome subunits in aged dermal human fibroblasts ameliorated the aged phenotype and restored the oxidized and ubiquitinated proteins to young levels. In the same way, transgenic mice with reduced proteasomal activity accumulated oxidized and ubiquitinated proteins, accelerating the aging phenotype and the age-related metabolic diseases (9). Besides, inhibition of proteasome activity impaired cell proliferation and shortened lifespan (10), reinforcing the importance of a correct proteostasis in healthy aging and longevity.

Recommendations

I. Exercise training

Training, for a minimum period of four weeks, activates autophagy and improves proteostasis in neurogenic myopathy

Considering that autophagy is impaired in neurogenic myopathy, we next set out to determine whether the re-establishment of autophagic flux is sufficient to improve skeletal muscle proteostasis and counteract SNC-induced skeletal muscle damage. We have recently demonstrated that exercise training is able to restore the autophagic flux in failing hearts contributing to better disease prognosis. To evaluate the effects of exercise training in autophagy in a model of neurogenic myopathy, rats were submitted to 4 weeks of moderate running training on a treadmill prior to SNC surgery.

II. Heat Shock Response

The highly conserved heat shock proteins (HSPs) are constitutively expressed and function as molecular chaperones which facilitate the synthesis and folding of proteins. They also participate in protein assembly, export, turn-over and regulation.

III. Plant Protein Source

Plant protein is simply a meaningful food source of protein which is from plants. This group can include pulses, tofu, soya, tempeh, seitan, nuts, seeds, certain grains and even peas. Pulses are a large group of plants, which include chickpeas, lentils, beans (such as black, kidney and adzuki beans) and split peas.

Plant proteins are highly nutritious – not only as good sources of protein, but also because they provide other nutrients such as fibre, vitamins and minerals. Our intake of fibre tends to be too low, however by incorporating certain plant proteins into your diet, such as pulses, peas and nuts, you can easily boost your fibre intake.

Conclusion

Proteostasis, a portmanteau of the words protein and homeostasis, is the concept that there are competing and integrated biological pathways within cells that control the biogenesis, folding, trafficking and degradation of proteins present within and outside the cell. Adapting proteostasis should enable the restoration of proteostasis once its loss leads to pathology. Cellular proteostasis is key to ensuring successful development, healthy aging, resistance to environmental stresses, and to minimize homeostasis perturbations by pathogens such as viruses.

Proteins inside any cell are packed together as tightly as passengers on the Tokyo subway at rush hour. Cell stressors can cause proteins to misfold, which in turn can cause them to aggregate and trigger disease. However, each cell also has stress sensors that attempt to restore “proteostasis”: proper protein folding. In two new reports, researchers provide hope that restoring proteostasis could help inhibit disease and aging some day.

About Global Citizen Capital

As a social impact investment fund vehicle, Global Citizen Capital and its portfolio companies adhere to an united theme of “From Sustainability to Regeneration”, delivering high quality of life to mankind. it strives to connect with individuals, companies, organizations, foundations and funds with the intention to generate a measurable, beneficial social or environmental impact alongside a financial return. Impact investments made also provide capital to address social and/or environmental issues. Global Citizen Capital is a leader in investments across the fields of preventive medicine and regenerative healthcare, and is active in the areas of social impact bonds, health credit markets and public-private sector partnerships to achieve its mandates.

About AWAWA

Bridging impact investments with charitable initiatives, Asia World Anti-Aging and Well-Being Association (“AWAWA”) has been established to support the research, mentorship and social outreach programs related to preventive healthcare. Working closely with global non-profits who share a similar mindset, AWAWA is dedicated to increasing the scale and effectiveness of impact investing around the world, building critical infrastructure and promoting activities, education, and research that help accelerate the development of a coherent impact investing industry in healthcare. Knowing the core drivers of healthcare costs are health sector expenditures (hospitals and physician costs) and the prevalence of long-term conditions, AWAWA works to reduce the financial burden on the healthcare system which can be lessened when the population becomes healthier.

References

1. Chuang SY, Lin CH, Fang JY. Natural compounds and aging: between autophagy and inflammasome. Biomed Res Int. (2014) 2014:297293. doi: 10.1155/2014/297293

2. Santos AL, Sinha S, Lindner AB. The good, the bad, and the ugly of ROS: new insights on aging and aging-related diseases from eukaryotic and prokaryotic model organisms. Oxid Med Cell Longev. (2018) 2018:1–23. doi: 10.1155/2018/1941285

3. Amm I. Protein quality control and elimination of protein waste: the role of the ubiquitin–proteasome system. Biochim Biophys Acta Mol Cell Res.(2014) 1843:182–96. doi: 10.1016/J.BBAMCR.2013.06.031

4. Kiffin R, Christian C, Knecht E, Cuervo AM. Activation of chaperone-mediated autophagy during oxidative stress. Mol Biol Cell (2004) 15:4829–40. doi: 10.1091/mbc.e04-06-0477

5. Glickman MH, Ciechanover A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev. (2002) 82:373–428. doi: 10.1152/physrev.00027.2001

6. Zhao J, Zhai B, Gygi SP, Goldberg AL. mTOR inhibition activates overall protein degradation by the ubiquitin proteasome system as well as by autophagy. Proc Natl Acad Sci USA. (2015) 112:15790–7. doi: 10.1073/pnas.1521919112

7. Chondrogianni N, Tzavelas C, Pemberton AJ, Nezis IP, Rivett AJ, Gonos ES. Overexpression of Proteasome β 5 Subunit Increases Amount of Assembled Proteasome and Confers Ameliorated Response to Oxidative Stress and Higher Survival Rates. (2005)

8. Hwang JS, Hwang JS, Chang I, Kim S. Age-associated decrease in proteasome content and activities in human dermal fibroblasts: restoration of normal level of proteasome subunits reduces aging markers in fibroblasts from elderly persons. J Gerontol Ser A Biol Sci Med Sci. (2007) 62:490–9. doi: 10.1093/gerona/62.5.490

9. Tomaru U, Takahashi S, Ishizu A, Miyatake Y, Gohda A, Suzuki S, et al. Decreased proteasomal activity causes age-related phenotypes and promotes the development of metabolic abnormalities. Am J Pathol. (2012) 180:963–72. doi: 10.1016/J.AJPATH.2011.11.012

10. Torres C, Lewis L, Cristofalo VJ. Proteasome inhibitors shorten replicative life span and induce a senescent-like phenotype of human fibroblasts. J Cell Physiol. (2006) 207:845–853. doi: 10.1002/jcp.20630