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Preface

This risk-benefit analysis (RBA) is part of Forever Healthy's "Rejuvenation Now" initiative that seeks to continuously identify new rejuvenation therapies and systematically evaluate them on their risks, benefits, procedures, and potential application.

Special thanks are extended to the whole Rejuvenation Now team at Forever Healthy for their friendly contributions.

Section 1: Overview 

Motivation

Phospholipids are an important structural component of cell and organelle membranes and play a role in many cell signaling pathways. Membranes incur oxidative damage over time and in several disease conditions. Oral and/or i.v. supplementation of phospholipids (particularly phosphatidylcholine) is hypothesized to repair this damage through the replacement of oxidized membrane phospholipids with "healthy" phospholipids, thus restoring or maintaining membrane integrity and function. 

Key questions 

This analysis seeks to answer the following questions:

• Which benefits result from phospholipid therapy (PLT)? 

• Which risks are involved in PLT (general and method-specific)?

• What are the potential risk mitigation strategies?

• Which method or combination of methods is the most effective for PLT?

• Which of the available methods are safe for use? 

• What is the best therapeutic protocol available at the moment?

• What is the best monitoring protocol currently available?

Impatient readers may choose to skip directly to Section 6 for the Presentation of Results and tips on practical application. 

Recommended reading/viewing

General introduction

The following sites offer information on PLT at a consumer level and are useful as an introduction to the topic:

• Mitochondria and the Anti-Aging Role Of Lipid Replacement Therapies - clinicaleducation.org

• Phosphatidylcholine (PPC/EPL) - heartfixer.com
  
  
  

Scientific overview 

The following scientific review provides a more detailed overview of the topic of PLT:

• Lipid Replacement Therapy: A natural medicine approach to replacing damaged lipids in cellular membranes and organelles and restoring function

Section 2: Methods

Analytic model

This RBA has been prepared based on the principles outlined in A Comprehensive Approach to Benefit-Risk Assessment in Drug Development (Sarac et al., 2012). 

Literature search

A literature search was conducted on Pubmed using the search terms shown in Table 1 and included articles available as of August 31, 2021. Titles and abstracts of the resulting studies were screened and relevant articles downloaded in full text. The references of the full-text articles were manually searched in order to identify additional trials that may have been missed by the search terms. Results reported in the book, Essential Phospholipids as a Membrane Therapeutic (Gundermann, 1993) were included as it summarized several clinical papers only available in other languages (see Table 3).

Many studies were published using brand names so we also included the brand names in our literature search. Please see Table 6 for a list of the brands we identified.

Inclusion criteria: Any clinical trial that used PLT, orally, or by i.v. was included. Meta-analyses that reported results from trials either in other languages or papers that were not available online were also included.

Exclusion criteria: We excluded animal and in vitro studies from the analysis because of an abundance of clinical trials as well as trials that used phospholipid s.c. injections for cosmetic purposes. 

Table 1: Literature search 

Abbreviation list

Section 3: Existing Evidence

Summary of results

Our search terms identified 3,665 studies of which 107 were relevant to this analysis (see Table 2). We also included the clinical studies summarized in Gundermann's book in our analysis following a discussion with the author, despite being unable to locate the majority of the original papers (see Table 3). Although PLT has long been used in medical practice, the quality of the evidence is quite low overall. For many papers, only the abstracts are available (in English) and many of the trials are observational. Most of the compounds administered for PLT contained several vitamins and minerals in addition to phospholipids, leading to difficulties in determining whether the benefits/risks occurred due to the phospholipid content or other components of the supplements and much of the research has been funded by producers of phospholipid supplements. Moreover, almost all of the trials were performed in subjects with preexisting health conditions making it difficult to determine the extent of the benefits in a healthy population.

Table 2: Clinical trials

Table 3: Gundermann summary

Section 4: Risk-Benefit Analysis

Decision model

Risk and benefit criteria

The decision profile is made up of risk and benefit criteria extracted from the outcomes of the above-mentioned papers. The benefit criteria are organized by category and type and are assessed according to magnitude, likelihood, duration, and perceived importance. The risk criteria are organized by category and type and are assessed according to severity, frequency of occurrence, and difficulty in detection and mitigation. Each criterion is assigned a numerical value for each assessment category:

1 = low 

2 = moderate

3 = high

The numerical values for the criterion are then summarized, serving as the justification for the weighting in the following column.

Weight

The criteria are weighted on a value scale to enable comparison (based on the relative importance of a difference). The value in the summary column is divided by 4 to result in a weight between 1 → 3.

Score

Each criterion is assessed according to the performance of PLT against the comparator (physiological aging) whereby a numerical value is assigned for each criterion -1 (inferior), 0 (equivalent or non-inferior), and +1 (superior) to the comparator.

Uncertainty

Uncertainty is determined according to the amount and quality of the evidence, availability of full text articles & supplementary data, number of participants and whether methodological flaws, conflicting studies, or conflicts of interest (i.e. funding) are present. Evidence that is based on RCTs is initially upgraded by 1 point, evidence from open-label trials is considered neutral, and evidence that is based on observational studies is downgraded by 1 point. The uncertainty is then further valued using the above-mentioned criteria to result in an uncertainty score. 

Weighted score

The weights and scores are multiplied to produce weighted scores that enable direct comparison (-3 → +3) and then adjusted according to the uncertainty score. Weighted scores are upgraded where the uncertainty score is low (positive) or downgraded where the uncertainty score is high (negative).

Benefit assessment 

We identified a total of 58 benefits associated with PLT. The benefits extended across several organ systems, were mostly of small magnitude and largely dependent on continued supplementation. Almost all benefits occurred in the context of pre-existing disease. There is limited evidence that the benefits would occur in healthy individuals. 

Table 4: Benefit assessment